David N. Cornfield

All Publications

• Intracellular Calcium Response to Oxytocin in Uterine Smooth Muscle Cells From Patients With Uterine Atony. Anesthesia and analgesia Ansari, J. R., Fornes, D., Obiyo, L. T., Michel, G., Cornfield, D. N. 2024

  View details for DOI 10.1213/ANE.0000000000007240

  View details for PubMedID 39495660

• miR-203 modulates pregnant myometrium contractility via transient receptor potential vanilloid 4 channel expression. FASEB journal : official publication of the Federation of American Societies for Experimental Biology Ying, L., Fornes, D. D., Dobberfuhl, A. D., Ansari, J. R., Alvira, C. M., Cornfield, D. N. 2024; 38 (22): e70173

  Abstract

  Preterm labor is the leading cause of neonatal death and major morbidity but remains a poorly understood process with no effective tocolytic therapies. Recent work has identified the transient receptor potential vanilloid 4 (TRPV4) channel, a membrane calcium channel upregulated in uterine smooth muscle through gestation, as integral in the transition from quiescence to contraction in the gravid uterus. The present study builds upon these findings and investigates regulation of the TRPV4 channel during pregnancy in the murine and human uterus by micro-RNA 203 (miR-203). We find a progressive decrease in miR-203 expression during gestation, accompanied by a reciprocal increase in TRPV4 mRNA and protein expression. In human uterine smooth muscle cells (UtSMC), miR-203 overexpression reduces, and si-RNA-mediated silencing increases, TRPV4 expression. Studies using murine UtSMC demonstrate that miR-203 expression modulates TRPV4-mediated cytosolic calcium entry and contractility. Consistent with these findings, the response to pharmacologic TRVP4 agonists is increased in myometrial tissue from miRNA203 -/- mice compared to control mice. Moreover, we demonstrate that miR-203 binds specifically on the promoter region of TRPV4 to decrease expression. In murine inflammatory models of preterm labor, miR-203 overexpression prolongs pregnancy. Estradiol (E2) decreases miR-203 and increases TRPV4 expression, providing a potential physiologic link for the unique reciprocal relationship in UtSMC. Taken together, these findings provide evidence that miR-203 modulates uterine contractility during pregnancy via negative regulation of TRPV4. These findings support the hypothesis that targeting miR-203 holds the promise of an entirely novel approach to prevent prematurity and treat preterm labor.

  View details for DOI 10.1096/fj.202401783RR

  View details for PubMedID 39545721

• Studying the Pulmonary Endothelium in Health and Disease. An Official American Thoracic Society Workshop Report. American journal of respiratory cell and molecular biology Hough, R. F., Alvira, C. M., Bastarache, J. A., Erzurum, S. C., Kuebler, W. M., Schmidt, E. P., Shimoda, L. A., Abman, S. H., Alvarez, D. F., Belvitch, P., Bhattacharya, J., Birukov, K. G., Chan, S. Y., Cornfield, D. N., Dudek, S. M., Garcia, J. G., Harrington, E. O., Hsia, C. C., Islam, M. N., Jonigk, D. D., Kalinichenko, V. V., Kolb, T. M., Lee, J. Y., Mammoto, A., Mehta, D., Rounds, S., Schupp, J. C., Shaver, C. M., Suresh, K., Tambe, D. T., Ventetuolo, C. E., Yoder, M. C., Stevens, T., Damarla, M. 2024

  Abstract

  Lung endothelium resides at the interface between the circulation and the underlying tissue, where it senses biochemical and mechanical properties of both the blood as it flows through the vascular circuit and the vessel wall. Endothelium performs the bidirectional signaling between the blood and tissue compartments that is necessary to maintain homeostasis while physically separating both, facilitating a tightly regulated exchange of water, solutes, cells, and signals. Disruption in endothelial function contributes to vascular disease, which can manifest in discrete vascular locations along the arterial-to-capillary-to-vein axis. While our understanding of mechanisms that contribute to endothelial cell injury and repair in acute and chronic vascular disease have advanced, pathophysiological mechanisms that underlie site-specific vascular disease remain incompletely understood. In an effort to improve the translatability of mechanistic studies of the endothelium, the American Thoracic Society convened a workshop to optimize rigor, reproducibility, and translation of discovery to advance our understanding of endothelial cell function in health and disease.

  View details for DOI 10.1165/rcmb.2024-0330ST

  View details for PubMedID 39189891

• Pediatric pulmonology: progress at the intersection of medicine and discovery. Current opinion in pediatrics Cornfield, D. N. 2024; 36 (3): 288-289

  View details for DOI 10.1097/MOP.0000000000001344

  View details for PubMedID 38655810

• Neonatal Hyperoxia Causes Pulmonary Hypertension and Increases Pulmonary Vascular Smooth Muscle Cell Calponin-1 Expression Dinh, D. T., Barnes, E. A., Fornes, D., Knutsen, C., Che, X., Zanini, F., Alvira, C. M., Cornfield, D. N. AMER THORACIC SOC. 2024

  View details for Web of Science ID 001277613400429

• VIEWING PULMONARY HYPERTENSION THROUGH A PEDIATRIC LENS. The European respiratory journal Agarwal, S., Fineman, J., Cornfield, D. N., Alvira, C. M., Zamanian, R. T., Goss, K., Yuan, K., Bonnet, S., Boucherat, O., Pullamsetti, S., Alcázar, M. A., Goncharova, E., Kudryashova, T. V., Nicolls, M. R., de Jesús Pérez, V. 2024

  View details for DOI 10.1183/13993003.01518-2023

  View details for PubMedID 38575157

• Nailfold capillaroscopy as a noninvasive tool for evaluating microvascular health in diabetes Rincon, G., Forst, M. L., Cornfield, D. N., Quake, S. R. CELL PRESS. 2024: 437A

  View details for Web of Science ID 001194120702520

• Effects of age on human capillaries Forst, M. L., Rincon, G., Cornfield, D. N., Quake, S. R. CELL PRESS. 2024: 437A

  View details for Web of Science ID 001194120702522

• MicroRNA-34a-Dependent Attenuation of Angiogenesis in Right Ventricular Failure. Journal of the American Heart Association Reddy, S., Hu, D. Q., Zhao, M., Ichimura, S., Barnes, E. A., Cornfield, D. N., Alejandre Alcázar, M. A., Spiekerkoetter, E., Fajardo, G., Bernstein, D. 2024: e029427

  Abstract

  The right ventricle (RV) is at risk in patients with complex congenital heart disease involving right-sided obstructive lesions. We have shown that capillary rarefaction occurs early in the pressure-loaded RV. Here we test the hypothesis that microRNA (miR)-34a, which is induced in RV hypertrophy and RV failure (RVF), blocks the hypoxia-inducible factor-1α-vascular endothelial growth factor (VEGF) axis, leading to the attenuated angiogenic response and increased susceptibility to RV failure.Mice underwent pulmonary artery banding to induce RV hypertrophy and RVF. Capillary rarefaction occurred immediately. Although hypoxia-inducible factor-1α expression increased (0.12±0.01 versus 0.22±0.03, P=0.05), VEGF expression decreased (0.61±0.03 versus 0.22±0.05, P=0.01). miR-34a expression was most upregulated in fibroblasts (4-fold), but also in cardiomyocytes and endothelial cells (2-fold). Overexpression of miR-34a in endothelial cells increased cell senescence (10±3% versus 22±2%, P<0.05) by suppressing sirtulin 1 expression, and decreased tube formation by 50% via suppression of hypoxia-inducible factor-1α, VEGF A, VEGF B, and VEGF receptor 2. miR-34a was induced by stretch, transforming growth factor-β1, adrenergic stimulation, and hypoxia in cardiac fibroblasts and cardiomyocytes. In mice with RVF, locked nucleic acid-antimiR-34a improved RV shortening fraction and survival half-time and restored capillarity and VEGF expression. In children with congenital heart disease-related RVF, RV capillarity was decreased and miR-34a increased 5-fold.In summary, miR-34a from fibroblasts, cardiomyocytes, and endothelial cells mediates capillary rarefaction by suppressing the hypoxia-inducible factor-1α-VEGF axis in RV hypertrophy/RVF, raising the potential for anti-miR-34a therapeutics in patients with at-risk RVs.

  View details for DOI 10.1161/JAHA.123.029427

  View details for PubMedID 38293915

• Hyperoxia prevents the dynamic neonatal increases in lung mesenchymal cell diversity. Scientific reports Zanini, F., Che, X., Suresh, N. E., Knutsen, C., Klavina, P., Xie, Y., Domingo-Gonzalez, R., Liu, M., Kum, A., Jones, R. C., Quake, S. R., Alvira, C. M., Cornfield, D. N. 2024; 14 (1): 2033

  Abstract

  Rapid expansion of the pulmonary microvasculature through angiogenesis drives alveolarization, the final stage of lung development that occurs postnatally and dramatically increases lung gas-exchange surface area. Disruption of pulmonary angiogenesis induces long-term structural and physiologic lung abnormalities, including bronchopulmonary dysplasia, a disease characterized by compromised alveolarization. Although endothelial cells are primary determinants of pulmonary angiogenesis, mesenchymal cells (MC) play a critical and dual role in angiogenesis and alveolarization. Therefore, we performed single cell transcriptomics and in-situ imaging of the developing lung to profile mesenchymal cells during alveolarization and in the context of lung injury. Specific mesenchymal cell subtypes were present at birth with increasing diversity during alveolarization even while expressing a distinct transcriptomic profile from more mature correlates. Hyperoxia arrested the transcriptomic progression of the MC, revealed differential cell subtype vulnerability with pericytes and myofibroblasts most affected, altered cell to cell communication, and led to the emergence of Acta1 expressing cells. These insights hold the promise of targeted treatment for neonatal lung disease, which remains a major cause of infant morbidity and mortality across the world.

  View details for DOI 10.1038/s41598-023-50717-w

  View details for PubMedID 38263350

  View details for PubMedCentralID PMC10805790

• Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth. Science advances Wang, C., Wang, Y. J., Ying, L., Wong, R. J., Quaintance, C. C., Hong, X., Neff, N., Wang, X., Biggio, J. R., Mesiano, S., Quake, S. R., Alvira, C. M., Cornfield, D. N., Stevenson, D. K., Shaw, G. M., Li, J. 2024; 10 (3): eadk1057

  Abstract

  Preterm birth affects ~10% of pregnancies in the US. Despite familial associations, identifying at-risk genetic loci has been challenging. We built deep learning and graphical models to score mutational effects at base resolution via integrating the pregnant myometrial epigenome and large-scale patient genomes with spontaneous preterm birth (sPTB) from European and African American cohorts. We uncovered previously unidentified sPTB genes that are involved in myometrial muscle relaxation and inflammatory responses and that are regulated by the progesterone receptor near labor onset. We studied genomic variants in these genes in our recruited pregnant women administered progestin prophylaxis. We observed that mutation burden in these genes was predictive of responses to progestin treatment for preterm birth. To advance therapeutic development, we screened ~4000 compounds, identified candidate molecules that affect our identified genes, and experimentally validated their therapeutic effects on regulating labor. Together, our integrative approach revealed the druggable genome in preterm birth and provided a generalizable framework for studying complex diseases.

  View details for DOI 10.1126/sciadv.adk1057

  View details for PubMedID 38241369

  View details for PubMedCentralID PMC10798565

• Intravenous Calcium to Decrease Blood Loss During Intrapartum Cesarean Delivery: A Randomized Controlled Trial. Obstetrics and gynecology Ansari, J. R., Yarmosh, A., Michel, G., Lyell, D., Hedlin, H., Cornfield, D. N., Carvalho, B., Bateman, B. T. 2023

  Abstract

  OBJECTIVE: To evaluate whether prophylactic administration of 1 g of intravenous calcium chloride after cord clamping reduces blood loss from uterine atony during intrapartum cesarean delivery.METHODS: This single-center, block-randomized, placebo-controlled, double-blind superiority trial compared the effects of 1 g intravenous calcium chloride with those of saline placebo control on blood loss at cesarean delivery. Parturients at 34 or more weeks of gestation requiring intrapartum cesarean delivery after oxytocin exposure in labor were enrolled. Calcium or saline placebo was infused over 10 minutes beginning 1minute after umbilical cord clamping in addition to standard care with oxytocin. The primary outcome was quantitative blood loss, analyzed by inverse Gaussian regression. Planned subgroup analysis excluded nonatonic bleeding, such as hysterotomy extension, arterial bleeding, and occult placenta accreta. We planned to enroll 120 patients to show a 200-mL reduction in quantitative blood loss in planned subgroup analysis, assuming up to 40% incidence of nonatonic bleeding (80% power, alpha<0.05).RESULTS: From April 2022 through March 2023, 828 laboring parturients provided consent and 120 participants were enrolled. Median blood loss was 840 mL in patients allocated to calcium chloride (n=60) and 1,051 mL in patients allocated to placebo (n=60), which was not statistically different (mean reduction 211 mL, 95% CI -33 to 410). In the planned subgroup analysis (n=39 calcium and n=40 placebo), excluding cases of surgeon-documented nonatonic bleeding, calcium reduced quantitative blood loss by 356 mL (95% CI 159-515). Rates of reported side effects were similar between the two groups (38% calcium vs 42% placebo).CONCLUSION: Prophylactic intravenous calcium chloride administered during intrapartum cesarean delivery after umbilical cord clamping did not significantly reduce blood loss in the primary analysis. However, in the planned subgroup analysis, calcium infusion significantly reduced blood loss by approximately 350 mL. These data suggest that this inexpensive and shelf-stable medication warrants future study as a novel treatment strategy to decrease postpartum hemorrhage, the leading global cause of maternal morbidity and mortality.CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT05027048.

  View details for DOI 10.1097/AOG.0000000000005441

  View details for PubMedID 37917943

• Loss of Prolyl Hydroxylase 1 and 2 in SM22α-Expressing Cells Prevents Hypoxia-Induced Pulmonary Hypertension. American journal of physiology. Lung cellular and molecular physiology Barnes, E. A., Ito, R., Che, X., Alvira, C. M., Cornfield, D. N. 2023

  Abstract

  Pulmonary arterial hypertension (PAH) is a disease characterized by increased vasoconstriction and vascular remodeling. Pulmonary artery smooth muscle cells (PASMC) highly express the transcription factor hypoxia inducible factor-1α (HIF-1α), yet the role of PASMC HIF-1α in the development of PAH remains controversial. To study the role of SMC HIF-1α in the pulmonary vascular response to acute and chronic hypoxia, we employed a gain of function strategy to stabilize HIF-1α in PASMC by generating mice lacking prolyl hydroxylase domain (PHD) 1 and 2 in SM22α-expressing cells. This strategy increased HIF-1α expression and transcriptional activity under conditions of normoxia and hypoxia. Acute hypoxia increased right ventricular systolic pressure (RVSP) in control, but not in SM22α-PHD1/2-/- mice. Chronic hypoxia increased RVSP and vascular remodeling more in control SM22α-PHD1/2+/+ than in SM22α-PHD1/2-/- mice. In vitro studies demonstrated increased contractility and myosin light chain phosphorylation in isolated PHD1/2+/+ compared to PHD1/2-/- PASMC under both normoxic and hypoxic conditions. After chronic hypoxia there was more p27 and less vascular remodeling in SM22α-PHD1/2-/- compared to SM22α-PHD1/2+/+ mice. Hypoxia increased p27 in PASMC isolated from control patients, but not in cells from patients with idiopathic PAH (IPAH). These findings highlight a SM22α-expressing cell specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling. Modulating HIF-1α expression in PASMC may represent a promising preventative and therapeutic strategy for patients with PAH.

  View details for DOI 10.1152/ajplung.00428.2022

  View details for PubMedID 37847687

• Delivering a New Future for People With Cystic Fibrosis. Pediatrics Burgener, E. B., Cornfield, D. N. 2023; 152 (4)

  Abstract

  Treatment, prognosis, and quality of life for people with cystic fibrosis (CF) have improved steadily since the initial description of the disease, but most dramatically in the past decade. In 2021, the median predicted survival increased to 53 years, compared with 17 years in 1970. The recent improvement in outcomes is attributable to the advent of cystic fibrosis transmembrane regulator (CFTR) modulators, small molecules that enhance the function of defective CFTR protein. The first CFTR modulator, ivacaftor, received Food and Drug Administration approval in 2011 to treat a single CFTR variant, comprising only 4% of those affected by CF. With the demonstration of efficacy, drug approval has been expanded to other variants. Multiple CFTR modulators used in combination with ivacaftor augment efficacy and increase the number of CFTR variants amenable to therapy. Approval of elexecaftor/tezecaftor/ivacaftor in 2019 increased the number of individuals who could benefit from highly effective modulator therapy (HEMT) to ∼90% of the CF population in the United States. HEMT has been dramatically effective, with overall improvements in lung function, quality of life, nutritional status, and, in women, increased fertility. HEMT may delay the onset of other CF-related comorbidities. Although off-target effects, including hepatotoxicity, drug-drug interactions, and putative mental health issues can complicate use, modulator therapy has been generally well tolerated. Ten percent of people with CF have variants that are not amenable to modulator treatment. HEMT, despite its great cost and limited global access, has brought legitimate hope and changed the lives of a significant majority of individuals and families affected by CF in North America.

  View details for DOI 10.1542/peds.2023-062985

  View details for PubMedID 37671451

  View details for PubMedCentralID PMC10522926

• ROLE OF TRPV4 IN MODULATING CALCIUM SIGNALING PATHWAYS IN NON-LABORING PREGNANT WOMEN: IMPLICATIONS FOR MYOMETRIAL CONTRACTILITY AND PRETERM LABOR MANAGEMENT Fornes, D., Ying, L., Ansari, J., Obiyo, L., Alvira, C., Cornfield, D. W B SAUNDERS CO LTD. 2023: E33-E34

  View details for Web of Science ID 001069701600103

• Hypoxia Inducible Factor-1α in SM22α Expressing Cells Modulates Alveolarization. American journal of respiratory cell and molecular biology Barnes, E. A., Knutsen, C., Kindt, A., Che, X., Ying, L., Adams, E., Gonzalez, E., Oak, P., Hilgendorff, A., Alvira, C. M., Cornfield, D. N. 2023

  Abstract

  Worldwide, the incidence of both preterm births and chronic lung disease of infancy, or bronchopulmonary dysplasia (BPD), remains high. Infants with BPD have larger and fewer alveoli, pathology that can persist into adulthood. Though hypoxia inducible factor-1α (HIF-1α) plays a significant role in mediating pulmonary angiogenesis and alveolarization, the cell specific role of HIF-1α remains incompletely understood.To determine whether HIF-1α, in a mesenchymal cells (MC) subset, mediates postnatal alveolarization.We generated mice with cell-specific deletion of HIF-1α by crossing SM22α-promoter-driven Cre mice with HIF-1αflox/flox mice (SM22α- HIF-1α-/-), determined SM22α-expressing cell identity using single cell RNA-seq, and interrogated clinical samples from preterm infants. Measurement and Main Outcomes: Deletion of HIF-1α in SM22α expressing cells had no effect on lung structure at day (d) 3 of life. However, at 8d there were fewer and larger alveoli, a difference that persisted into adulthood. Microvascular density, elastin organization, and peripheral branching of the lung vasculature were decreased in SM22α-HIF-1α-/-, compared to control, mice. Single cell RNA-seq demonstrated that 3 MC subtypes (myofibroblasts, airway and vascular smooth muscle cells (VSMC)) express SM22α. Pulmonary VSMC from SM22α- HIF-1α-/- had decreased angiopoetin 2 expression and, in co-culture experiments, a diminished capacity to promote angiogenesis that was rescued by angiopoetin-2. Angiopoetin-2 expression in the tracheal aspirates of preterm infants was inversely correlated with overall time on mechanical ventilation, a marker of disease severity.SM22α-specific HIF-1α expression drives peripheral angiogenesis and alveolarization in the lung, perhaps by promoting angiopoetin-2 expression.

  View details for DOI 10.1165/rcmb.2023-0045OC

  View details for PubMedID 37290124

• Alterations of Aerocyte Capillary Phenotype During Postnatal Development and in Response to Injury Zhang, D., Che, X., Knutsen, C., Liu, M., Suresh, N. E., Saito, T., Cornfield, D., Zanini, F., Alvira, C. M. AMER THORACIC SOC. 2023

  View details for Web of Science ID 000995814707161

• Developmental Expression of Paternally Expressed Gene-3 Promotes Angiogenic Function in General Capillary Endothelial Cells From the Early Alveolar Lung Liu, M., Knutsen, C., Che, X., Cornfield, D. N., Zanini, F., Alvira, C. M. AMER THORACIC SOC. 2023

  View details for Web of Science ID 000995814704135

• Long-Standing Alterations in Pulmonary Vascular Cell Phenotype and Cell-Cell Communication Upon Recovery From Acute Hyperoxia Defined at Single-Cell Resolution Knutsen, C., Che, X., Liu, M., Zanini, F., Cornfield, D. N., Alvira, C. M. AMER THORACIC SOC. 2023

  View details for Web of Science ID 000995814701234

• Neonatal Hyperoxia Causes Vascular Smooth Muscle Specific Transcriptomic Changes and Pulmonary Hypertension Dinh, D. T., Barnes, E. A., Ito, R., Knutsen, C., Che, X., Zanini, F., Alvira, C. M., Cornfield, D. N. AMER THORACIC SOC. 2023

  View details for Web of Science ID 000995814705361

• WNT7A deficit is associated with dysfunctional angiogenesis in pulmonary arterial hypertension. The European respiratory journal Chakraborty, A., Nathan, A., Orcholski, M., Agarwal, S., Shamskhou, E. A., Auer, N., Mitra, A., Guardado, E. S., Swaminathan, G., Condon, D. F., Yu, J., McCarra, M., Juul, N. H., Mallory, A., Guzman-Hernandez, R. A., Yuan, K., Rojas, V., Crossno, J. T., Yung, L., Yu, P. B., Spencer, T., Winn, R. A., Frump, A., Karoor, V., Lahm, T., Hedlin, H., Fineman, J. R., Lafyatis, R., Knutsen, C. N., Alvira, C. M., Cornfield, D. N., de Jesus Perez, V. A. 2023

  Abstract

  INTRODUCTION: Pulmonary arterial hypertension (PAH) is characterized by loss of microvessels. The Wnt pathways control pulmonary angiogenesis, but their role in PAH is incompletely understood. We hypothesized that Wnt activation in pulmonary microvascular endothelial cells (PMVECs) is required for pulmonary angiogenesis, and its loss contributes to PAH.METHODS: Lung tissue and PMVECs from healthy and PAH patients were screened for Wnt production. Global and endothelial-specific Wnt7a-/- mice were generated and exposed to chronic hypoxia and Sugen-hypoxia (SuHx).RESULTS: Healthy PMVECs demonstrated >6-fold Wnt7a expression during angiogenesis that was absent in PAH PMVECs and lungs. Wnt7a expression correlated with formation of tip cells, a migratory endothelial phenotype critical for angiogenesis. PAH PMVECs demonstrated reduced VEGF-induced tip cell formation as evidenced by reduced filopodia formation and motility, which was partially rescued by recombinant Wnt7a. We discovered that Wnt7a promotes VEGF signaling by facilitating Y1175 tyrosine phosphorylation in VEGFR2 through ROR2, a Wnt-specific receptor. We found that ROR2 knockdown mimics Wnt7a insufficiency and prevents recovery of tip cell formation with Wnt7a stimulation. While there was no difference between wild-type and endothelial-specific Wnt7a-/- mice under either chronic hypoxia and SuHx, global Wnt7a+/- mice in hypoxia demonstrated higher pulmonary pressures and severe right ventricular and lung vascular remodeling. Similar to PAH, Wnt7a+/- PMVECs exhibited insufficient angiogenic response to VEGF-A that improved with Wnt7a.CONCLUSIONS: Wnt7a promotes VEGF signaling in lung PMVECs and its loss is associated with insufficient VEGF-A angiogenic response. We propose that Wnt7a deficiency contributes to progressive small vessel loss in PAH.

  View details for DOI 10.1183/13993003.01625-2022

  View details for PubMedID 37024132

• Developmental diversity and unique sensitivity to injury of lung endothelial subtypes during postnatal growth. iScience Zanini, F., Che, X., Knutsen, C., Liu, M., Suresh, N. E., Domingo-Gonzalez, R., Dou, S. H., Zhang, D., Pryhuber, G. S., Jones, R. C., Quake, S. R., Cornfield, D. N., Alvira, C. M. 2023; 26 (3): 106097

  Abstract

  At birth, the lung is still immature, heightening susceptibility to injury but enhancing regenerative capacity. Angiogenesis drives postnatal lung development. Therefore, we profiled the transcriptional ontogeny and sensitivity to injury of pulmonary endothelial cells (EC) during early postnatal life. Although subtype speciation was evident at birth, immature lung EC exhibited transcriptomes distinct from mature counterparts, which progressed dynamically over time. Gradual, temporal changes in aerocyte capillary EC (CAP2) contrasted with more marked alterations in general capillary EC (CAP1) phenotype, including distinct CAP1 present only in the early alveolar lung expressing Peg3, a paternally imprinted transcription factor. Hyperoxia, an injury that impairs angiogenesis induced both common and unique endothelial gene signatures, dysregulated capillary EC crosstalk, and suppressed CAP1 proliferation while stimulating venous EC proliferation. These data highlight the diversity, transcriptomic evolution, and pleiotropic responses to injury of immature lung EC, possessing broad implications for lung development and injury across the lifespan.

  View details for DOI 10.1016/j.isci.2023.106097

  View details for PubMedID 36879800

  View details for PubMedCentralID PMC9984561

• Fat Embolism Syndrome After Knee Arthroscopy in a Pediatric Patient. Chest Bassell-Hawkins, J., Suresh, N. E., Mahoney, D., Van Hentenryck, M., Csortan, A., Pena, D., Cornfield, D. N. 2023; 163 (3): e107-e110

  Abstract

  Fat embolism syndrome describes a constellation of symptoms that follow an insult and that results in a triad of respiratory distress, neurologic symptoms, and petechia. The antecedent insult usually entails trauma or orthopedic procedure, most frequently involving long bone (especially the femur) and pelvic fractures. The underlying mechanism of injury remains unknown but entails biphasic vascular injury with vascular obstruction from fat emboli followed by an inflammatory response. We present an unusual case of a pediatric patient with acute onset of altered mental status, respiratory distress, hypoxemia, and subsequent retinal vascular occlusions after knee arthroscopy and lysis of adhesions. Diagnostic findings most supportive of the fat embolism syndrome included anemia, thrombocytopenia, pulmonary parenchymal, and cerebral pathologic findings on imaging studies. This case highlights the importance of fat embolism syndrome as a diagnostic consideration after an orthopedic procedure, even absent major trauma or long bone fracture.

  View details for DOI 10.1016/j.chest.2022.10.018

  View details for PubMedID 36894263

• Rare to Ubiquitinous: Alveolar Capillary Dysplasia, FOXF1 and a Sly Approach to Angiogenesis. American journal of respiratory and critical care medicine Cornfield, D. N., Nogee, L. M. 2023

  View details for DOI 10.1164/rccm.202212-2273ED

  View details for PubMedID 36608259

• Transient Receptor Potential Vanilloid 4 Channel Blockade Decreases Contractility of the Pregnant Human Myometrium Ying, L., Fornes, D., Obiyo, L. T., Ansari, J., Alvira, C. M., Cornfield, D. N. SPRINGER HEIDELBERG. 2023: 112A-113A

  View details for Web of Science ID 001043029500176

• SM22α cell specific HIF stabilization mitigates hyperoxia-induced neonatal lung injury. American journal of physiology. Lung cellular and molecular physiology Ito, R., Barnes, E. A., Che, X., Alvira, C. M., Cornfield, D. N. 2022

  Abstract

  In premature infants the incidence of chronic lung disease of infancy, or bronchopulmonary dysplasia (BPD), remains high. Histologically BPD is characterized by larger and fewer alveoli. Hypoxia-inducible factors (HIF) play a role in alveolarization, but cell specific effects of HIF expression in neonatal lung injury remain unknown. Thus, we sought to determine whether HIF stabilization in SM22α expressing cells mitigates hyperoxia-induced neonatal lung injury. We crossed SM22α-promotor-driven Cre recombinase mice with prolyl hydroxylase (PHD) PHD1flox/flox and PHD2flox/flox mice. Neonatal mice were randomized to 21% O2 (normoxia) or 80% O2 (hyperoxia) exposure for 14 days, with longer term studies (hyperoxia recovery) performed on mice recovered in normoxia for 10 weeks. SM22α-specific HIF stabilization mitigated hyperoxia-induced lung injury and preserved microvessel density compared to control mice. In SM22α-PHD1/2-/- mice, pulmonary artery endothelial cells (PAEC) were more proliferative and pulmonary arteries expressed more collagen IV compared to control mice. Angiopoietin-2 (Ang2) mRNA expression in pulmonary artery smooth muscle cells (PASMC) was greater in SM22α-PHD1/2-/- compared to control mice. Co-culture of PEC with PASMC isolated from SM22α-PHD1/2-/- mice increased angiogenesis compared to PEC co-cultured with control PASMC. Cell-specific deletion of PHD 1 and 2 selectively increases HIF-1α expression in SM22α expressing cells and protects neonatal lung development despite prolonged hyperoxia exposure. HIF stabilization in SM22α expressing cells preserved endothelial cell proliferation, microvascular density, increased angiopoetin-2 expression, and lung structure, suggesting a role for cell-specific HIF-1α stabilization to prevent neonatal lung injury.

  View details for DOI 10.1152/ajplung.00110.2022

  View details for PubMedID 35762602

• Interstitial Lung Disease Caused by STING-Associated Vasculopathy with Onset in Infancy Lee, L., Cornfield, D. N. AMER THORACIC SOC. 2022

  View details for Web of Science ID 000792480401004

• Pharmacologic Inhibition of Wnt Signaling in a Murine Model of Pulmonary Hypertension Halts Neointimal Growth and Causes Neointimal Lesion Regression in Pulmonary Arteries Steffes, L. C., Cornfield, D. N., Kumar, M. E. AMER THORACIC SOC. 2022

  View details for Web of Science ID 000792480406009

• A low-cost, highly functional, emergency use ventilator for the COVID-19 crisis. PloS one Raymond, S. J., Baker, S., Liu, Y., Bustamante, M. J., Ley, B., Horzewski, M. J., Camarillo, D. B., Cornfield, D. N. 2022; 17 (3): e0266173

  Abstract

  Respiratory failure complicates most critically ill patients with COVID-19 and is characterized by heterogeneous pulmonary parenchymal involvement, profound hypoxemia and pulmonary vascular injury. The high incidence of COVID-19 related respiratory failure has exposed critical shortages in the supply of mechanical ventilators, and providers with the necessary skills to treat. Traditional mass-produced ventilators rely on an internal compressor and mixer to moderate and control the gas mixture delivered to a patient. However, the current emergency has energized the pursuit of alternative designs, enabling greater flexibility in supply chain, manufacturing, storage, and maintenance considerations. To achieve this, we hypothesized that using the medical gasses and flow interruption strategy would allow for a high performance, low cost, functional ventilator. A low-cost ventilator designed and built-in accordance with the Emergency Use guidance from the US Food and Drug Administration (FDA) is presented wherein pressurized medical grade gases enter the ventilator and time limited flow interruption determines the ventilator rate and tidal volume. This simple strategy obviates the need for many components needed in traditional ventilators, thereby dramatically shortening the time from storage to clinical deployment, increasing reliability, while still providing life-saving ventilatory support. The overall design philosophy and its applicability in this new crisis is described, followed by both bench top and animal testing results used to confirm the precision, safety and reliability of this low cost and novel approach to mechanical ventilation. The ventilator meets and exceeds the critical requirements included in the FDA emergency use guidelines. The ventilator has received emergency use authorization from the FDA.

  View details for DOI 10.1371/journal.pone.0266173

  View details for PubMedID 35353851

• Micro-RNA 203 Regulates Myometrial Smooth Muscle Cell Expression of the Transient Receptor Vanilloid 4 Channel and Contractility. Ying, L., Alvira, C. M., Cornfield, D. N. SPRINGER HEIDELBERG. 2021: 122A

  View details for Web of Science ID 000675441000191

• Coronavirus disease 2019 respiratory disease in children: clinical presentation and pathophysiology. Current opinion in pediatrics Steffes, L. C., Cornfield, D. N. 2021; 33 (3): 302–10

  Abstract

  PURPOSE OF REVIEW: Pediatric coronavirus disease 2019 (COVID-19) respiratory disease is a distinct entity from adult illness, most notable in its milder phenotype. This review summarizes the current knowledge of the clinical patterns, cellular pathophysiology, and epidemiology of COVID-19 respiratory disease in children with specific attention toward factors that account for the maturation-related differences in disease severity.RECENT FINDINGS: Over the past 14 months, knowledge of the clinical presentation and pathophysiology of COVID-19 pneumonia has rapidly expanded. The decreased disease severity of COVID-19 pneumonia in children was an early observation. Differences in the efficiency of viral cell entry and timing of immune recognition and response between children and adults remain at the center of ongoing research.SUMMARY: The clinical spectrum of COVID-19 respiratory disease in children is well defined. The age-related differences protecting children from severe disease and death remain incompletely understood.

  View details for DOI 10.1097/MOP.0000000000001013

  View details for PubMedID 33938476

• Editorial: Covid-19 and respiratory illness in children: seeking knowledge, discerning truth. Current opinion in pediatrics Cornfield, D. N. 2021; 33 (3): 292–93

  View details for DOI 10.1097/MOP.0000000000001014

  View details for PubMedID 33938474

• The Effect of Combining Business Training, Microfinance, and Support Group Participation on Economic Status and Intimate Partner Violence in an Unplanned Settlement of Nairobi, Kenya JOURNAL OF INTERPERSONAL VIOLENCE Sarnquist, C. C., Ouma, L., Lang'at, N., Lubanga, C., Sinclair, J., Baiocchi, M. T., Cornfield, D. N. 2021; 36 (7-8): 3903–21

  View details for DOI 10.1177/0886260518779067

  View details for Web of Science ID 000630100900065

• Mentor-Mentee interactions: a 2-way street. The APS-SPR virtual chat series. Pediatric research Cornfield, D. N., October, T. W., Libby, A. M., Abman, S. H. 2021

  View details for DOI 10.1038/s41390-021-01431-8

  View details for PubMedID 33731818

• Bronchopulmonary Dysplasia: Then, Now, and Next. Pediatric allergy, immunology, and pulmonology Tracy, M. C., Cornfield, D. N. 2020; 33 (3): 99-109

  Abstract

  Bronchopulmonary dysplasia (BPD) has evolved considerably since its first description over 50 years ago. This review aims to provide a historical framework for conceptualizing BPD and a current understanding of the changing definition, epidemiology, pathophysiology, treatment, and outcomes of BPD. The transdisciplinary approach that led to the initial phenotypic description of BPD continues to hold promise today. Investigators are refining the definition of BPD in light of changes in clinical care and increasing survival rates of very preterm infants. Despite improvements in perinatal care the incidence of BPD continues to increase. There is growing recognition that antenatal risk factors play a key role in the development of BPD. Strategies designed to prevent or limit neonatal lung injury continue to evolve. Defining the phenotype of infants with BPD can meaningfully direct treatment. Infants with BPD benefit from an interdisciplinary approach to longitudinal care with a focus on growth and neurocognitive development. While the ultimate impact of BPD on long-term pulmonary morbidity remains an active area of investigation, current data indicate that most children and adolescents with a history of BPD have a quality of life comparable to that of other preterm infants.

  View details for DOI 10.1089/ped.2020.1205

  View details for PubMedID 35922031

• Diverse homeostatic and immunomodulatory roles of immune cells in the developing mouse lung at single cell resolution. eLife Domingo-Gonzalez, R., Zanini, F., Che, X., Liu, M., Jones, R. C., Swift, M. A., Quake, S. R., Cornfield, D. N., Alvira, C. M. 2020; 9

  Abstract

  At birth, the lungs rapidly transition from a pathogen-free, hypoxic environment to a pathogen-rich, rhythmically distended air-liquid interface. Although many studies have focused on the adult lung, the perinatal lung remains unexplored. Here, we present an atlas of the murine lung immune compartment during early postnatal development. We show that the late embryonic lung is dominated by specialized proliferative macrophages with a surprising physical interaction with the developing vasculature. These macrophages disappear after birth and are replaced by a dynamic mixture of macrophage subtypes, dendritic cells, granulocytes, and lymphocytes. Detailed characterization of macrophage diversity revealed an orchestration of distinct subpopulations across postnatal development to fill context-specific functions in tissue remodeling, angiogenesis, and immunity. These data both broaden the putative roles for immune cells in the developing lung and provide a framework for understanding how external insults alter immune cell phenotype during a period of rapid lung growth and heightened vulnerability.

  View details for DOI 10.7554/eLife.56890

  View details for PubMedID 32484158

• Editorial: Pediatric Pulmonology 2020, replacing fear with hope! Current opinion in pediatrics Cornfield, D. N. 2020; 32 (3): 376–77

  View details for DOI 10.1097/MOP.0000000000000899

  View details for PubMedID 32371840

• Pulmonary Artery Smooth Muscle Cell Bone Morphogenetic Protein 2 Promotes Pulmonary Endothelial Cell Migration and Angiogenesis Barnes, E., Cornfield, D. WILEY. 2020

  View details for DOI 10.1096/fasebj.2020.34.s1.05796

  View details for Web of Science ID 000546023101439

• Dynamic MicroRNA 203 Expression Regulates Myometrial Smooth Muscle Cell Transient Receptor Vanilloid 4 Channel Expression During Pregnancy. Ying, L., Ingles, J. A., Alvira, C. M., Cornfield, D. N. SPRINGER HEIDELBERG. 2020: 68A

  View details for Web of Science ID 000525432600027

• Extracellular Calcium Entry via the TRPV4 Channel Potentiates NF kappa B Activation in the Myometrium. Ingles, J. A., Rodriguez, S., Ying, L., Cornfield, D. N., Alvira, C. M. SPRINGER HEIDELBERG. 2020: 109A

  View details for Web of Science ID 000525432600132

• Mucus plugging, air trapping, and bronchiectasis are important outcome measures in assessing progressive childhood cystic fibrosis lung disease. Pediatric pulmonology Robinson, T. E., Goris, M. L., Moss, R. B., Tian, L., Kan, P., Yilma, M., McCoy, K. S., Newman, B., de Jong, P. A., Long, F. R., Brody, A. S., Behrje, R., Yates, D. P., Cornfield, D. N. 2020

  Abstract

  OBJECTIVE: To determine which outcome measures could detect early progression of disease in school-age children with mild cystic fibrosis (CF) lung disease over a two-year time interval utilizing chest computed tomography (CT) scores, quantitative CT air trapping (QAT), and spirometric measurements.METHODS: Thirty-six school-age children with mild CF lung disease (median [interquartile range] age 12 [3.7] years; percent predicted forced expiratory volume in 1second (ppFEV1 ) 99 [12.5]) were evaluated by serial spirometer-controlled chest CT scans and spirometry at baseline, 3-month, 1- and 2-years.RESULTS: No significant changes were noted at 3-month for any variable except for decreased ppFEV1 . Mucus plugging score (MPS) and QATA1 and A2 increased at 1- and 2-years. The bronchiectasis score (BS), and total score (TS) were increased at 2-year. All variables tested with the exception of bronchial wall thickness score, parenchymal score (PS), and ppFEV1 , were consistent with longitudinal worsening of lung disease. Multivariate analysis revealed baseline PS, baseline TS, and 1-year changes in BS and air trapping score were predictive of 2-year changes in BS.CONCLUSIONS: MPS and QATA1-A2 were the most sensitive indicators of progressive childhood CF lung disease. The 1-year change in the bronchiectasis score had the most positive predictive power for 2-year change in bronchiectasis.

  View details for DOI 10.1002/ppul.24646

  View details for PubMedID 31962004

• Defining Neointimal Heterogeneity and the Signals Driving Vasculopathy in Pulmonary Hypertension Steffes, L. C., Cornfield, D. N., Kumar, M. AMER THORACIC SOC. 2020

  View details for Web of Science ID 000556622801358

• Vitamin D: Feel it in More Than Just Your Bones! American journal of respiratory cell and molecular biology Cornfield, D. N. 2020

  View details for DOI 10.1165/rcmb.2020-0072ED

  View details for PubMedID 32160008

• REDUCING OFF-LABEL DORNASE ALFA UTILIZATION THROUGH COMPUTERIZED ORDER ENTRY OPTIMIZATION Moss, J., Gaskari, S., Cornfield, D., Hammer, G. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000530000201673

• A proposal for the addressing the needs of the pediatric pulmonary work force. Pediatric pulmonology Gaston, B. n., Laguna, T. A., Noah, T. L., Hagood, J. n., Voynow, J. n., Ferkol, T. n., Hershenson, M. n., Boyne, K. n., Delecaris, A. n., Ross, K. n., Gozal, D. n., Celedón, J. C., Abman, S. H., Moore, P. n., Davis, S. n., Cornfield, D. N., Murphy, T. n. 2020

  Abstract

  Unprecedented opportunities and daunting difficulties are anticipated in the future of pediatric pulmonary medicine. To address these issues and optimize pediatric pulmonary training, a group of faculty from various institutions met in 2019 and proposed specific, long-term solutions to the emerging problems in the field. Input on these ideas was then solicited more broadly from faculty with relevant expertise and from recent trainees. This proposal is a synthesis of these ideas. Pediatric pulmonology was among the first pediatric specialties to be grounded deliberately in science, requiring its fellows to demonstrate expertise in scientific inquiry (1). In the future, we will need more training in science, not less. Specifically, the scope of scientific inquiry will need to be broader. The proposal outlined below is designed to help optimize the practices of current providers and to prepare the next generation to be leaders in pediatric care in the future. We are optimistic that this can be accomplished. Our broad objectives are (a) to meet the pediatric subspecialty workforce demand by increasing interest and participation in pediatric pulmonary training; (b) to modernize training to ensure that future pediatric pulmonologists will be prepared clinically and scientifically for the future of the field; (c) to train pediatric pulmonologists who will add value in the future of pediatric healthcare, complemented by advanced practice providers and artificial intelligence systems that are well-informed to optimize quality healthcare delivery; and (d) to decrease the cost and improve the quality of care provided to children with respiratory diseases.

  View details for DOI 10.1002/ppul.24856

  View details for PubMedID 32531116

• Bronchopulmonary Dysplasia: Then, Now, and Next Pediatric Allergy, Immunology, and Pulmonology Tracy, M. C., Cornfield, D. N. 2020; 33 (3): 99-109

  View details for DOI 10.1089/ped.2020.1205

• Three Infants with Pathogenic Variants in the ABCA3 Gene: Presentation, Treatment and Clinical Course. The Journal of pediatrics Si, n. n., X, n. n., Steffes, n. n., L C, n. n., Schymick, n. n., J C, n. n., Hazard, n. n., F K, n. n., Tracy, n. n., M C, n. n., Cornfield, n. n., D N, n. n. 2020

  View details for DOI 10.1016/j.jpeds.2020.12.055

  View details for PubMedID 33359301

• Novel Prescriptions From Medical Schools for Physician-Scientist Training and Engagement in the Twenty-First Century. Academic medicine : journal of the Association of American Medical Colleges Simpson, R. L., Cornfield, D. N., Burris, J. E. 2020; Publish Ahead of Print

  Abstract

  Physicians engaged in biomedical research are well positioned to directly focus the discovery process on human biology. However, the relative proportion of investigators engaged in both caring for patients and conducting research is decreasing. To address the dwindling numbers of physician-scientists nationally, the Burroughs Wellcome Fund (BWF) created the Physician-Scientist Institutional Awards Program by dedicating 25 million dollars to new initiatives at 10 degree-granting, accredited medical schools in North America, awarded on the basis of institutions' proposals. The perceived barriers to physician-scientist training, program initiatives, and commitment to training a diverse group of future researchers were articulated in each application. In all, the BWF review committee considered 136 distinct proposals from 83 medical schools, representing 54% of all accredited medical schools in North America. Barriers identified by more than one-third of the applicant institutions included the absence of both mentors and role models, student indebtedness, institutional cultures that valued clinical care delivery above the discovery process, limited prior relevant research experience, and structural barriers that limited scheduling flexibility during training. Awards were granted to institutions with programs designed to be sustainable and overcome critical, prospectively identified barriers to training and retention of physician-scientists. Potential solutions from the 10 funded programs were focused on different stages of the training experience. Though a determination about the relative success of each of the initiatives will take many years, careful consideration of the barriers identified and more general application of specific program component may be beneficial in increasing the numbers of physicians actively involved in biomedical research.

  View details for DOI 10.1097/ACM.0000000000003906

  View details for PubMedID 33369904

• Pediatric pulmonology, ever changing, but happily in the same, old boat. Current opinion in pediatrics Cornfield, D. N. 2019

  View details for PubMedID 30950851

• Loss of TPRV4 Attenuates NF kappa B Activation and Inflammation Thereby Decreasing Murine Susceptibility to LPS-Induced Preterm Labor. Ingles, J. A., Rodriguez, Z., Ying, L., Cornfield, D. N., Alvira, C. M. SAGE PUBLICATIONS INC. 2019: 110A

  View details for Web of Science ID 000459610400138

• Usability of a Novel Digital Asthma Management Program Harris, B. U., Carchia, M., Huffaker, M. F., Cornfield, D. N. MOSBY-ELSEVIER. 2019: AB170

  View details for DOI 10.1016/j.jaci.2018.12.521

  View details for Web of Science ID 000457771200514

• Editorial: Pediatric pulmonology, ever changing, but happily in the same, old boat. Current opinion in pediatrics Cornfield, D. N. 2019; 31 (3): 328–29

  View details for DOI 10.1097/MOP.0000000000000761

  View details for PubMedID 31090573

• More than BPD? Diagnosis, Prognosis and Treatment of ABCA3 Deficiency in an Extremely Premature Infant Steffes, L. C., Tracy, M., Cornfield, D. N. AMER THORACIC SOC. 2019

  View details for Web of Science ID 000466776701221

• Overexpression of Hypoxia Inducible Factors in Pulmonary Artery Smooth Muscle Cells Mitigates Hypoxia-Induced Pulmonary Hypertension Barnes, E. A., Che, X., Ito, R., Reddy, S., Cornfield, D. N. AMER THORACIC SOC. 2019

  View details for Web of Science ID 000466776701480

• Pulmonary artery smooth muscle cell HIF-1alpha regulates endothelin expression via microRNA-543. American journal of physiology. Lung cellular and molecular physiology Wang, C., Ying, L., Barnes, E. A., Adams, E. S., Kim, F. Y., Engel, K. W., Alvira, C. M., Cornfield, D. N. 2018; 315 (3): L422–L431

  Abstract

  Pulmonary artery smooth muscle cells (PASMCs) express endothelin (ET-1), which modulates the pulmonary vascular response to hypoxia. Although cross-talk between hypoxia-inducible factor-1alpha (HIF-1alpha), an O2-sensitive transcription factor, and ET-1 is established, the cell-specific relationship between HIF-1alpha and ET-1 expression remains incompletely understood. We tested the hypotheses that in PASMCs 1) HIF-1alpha expression constrains ET-1 expression, and 2) a specific microRNA (miRNA) links HIF-1alpha and ET-1 expression. In human (h)PASMCs, depletion of HIF-1alpha with siRNA increased ET-1 expression at both the mRNA and protein levels ( P < 0.01). In HIF-1alpha-/- murine PASMCs, ET-1 gene and protein expression was increased ( P < 0.0001) compared with HIF-1alpha+/+ cells. miRNA profiles were screened in hPASMCs transfected with siRNA-HIF-1alpha, and RNA hybridization was performed on the Agilent (Santa Clara, CA) human miRNA microarray. With HIF-1alpha depletion, miRNA-543 increased 2.4-fold ( P < 0.01). In hPASMCs, miRNA-543 overexpression increased ET-1 gene ( P < 0.01) and protein ( P < 0.01) expression, decreased TWIST gene expression ( P < 0.05), and increased ET-1 gene and protein expression, compared with nontargeting controls ( P < 0.01). Moreover, we evaluated low passage hPASMCs from control and patients with idiopathic pulmonary arterial hypertension (IPAH). Compared with controls, protein expression of HIF-1alpha and Twist-related protein-1 (TWIST1) was decreased ( P < 0.05), and miRNA-543 and ET-1 expression increased ( P < 0.001) in hPASMCs from patients with IPAH. Thus, in PASMCs, loss of HIF-1alpha increases miRNA-543, which decreases Twist expression, leading to an increase in PASMC ET-1 expression. This previously undescribed link between HIF-1alpha and ET-1 via miRNA-543 mediated Twist suppression represents another layer of molecular regulation that might determine pulmonary vascular tone.

  View details for PubMedID 29745253

• Pulmonary artery smooth muscle cell HIF-1 alpha regulates endothelin expression via microRNA-543 AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Wang, C., Ying, L., Barnes, E. A., Adams, E. S., Kim, F. Y., Engel, K. W., Alvira, C. M., Cornfield, D. N. 2018; 315 (3): L422–L431

  View details for DOI 10.1152/ajplung.00475.2017

  View details for Web of Science ID 000443901300009

• Settling the Score in Pulmonary Hypertension? Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Hopper, R. K., Cornfield, D. N. 2018; 19 (8): 782–83

  View details for PubMedID 30095716

• Passive Nocturnal Physiologic Monitoring Enables Early Detection of Exacerbations in Children with Asthma A Proof-of-Concept Study AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Huffaker, M. F., Carchia, M., Harris, B. U., Kethman, W. C., Murphy, T. E., Sakarovitch, C. D., Qin, F., Cornfield, D. N. 2018; 198 (3): 320–28

  View details for DOI 10.1164/rccm.201712-2606OC

  View details for Web of Science ID 000440607200012

• Settling the Score in Pulmonary Hypertension?* PEDIATRIC CRITICAL CARE MEDICINE Hopper, R. K., Cornfield, D. N. 2018; 19 (8): 782–83

  View details for DOI 10.1097/PCC.0000000000001651

  View details for Web of Science ID 000440946300025

• beta 1-Subunit of the calcium-sensitive potassium channel modulates the pulmonary vascular smooth muscle cell response to hypoxia AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Barnes, E. A., Lee, L., Barnes, S. L., Brenner, R., Alvira, C. M., Cornfield, D. N. 2018; 315 (2): L265–L275

  View details for DOI 10.1152/ajplung.00060.2018

  View details for Web of Science ID 000442116600002

• An amyloidogenic hexapeptide derived from amylin attenuates inflammation and acute lung injury in murine sepsis PLOS ONE Mahapatra, S., Ying, L., Ho, P., Kurnellas, M., Rothbard, J., Steinman, L., Cornfield, D. N. 2018; 13 (7): e0199206

  Abstract

  Although the accumulation of amyloidogenic proteins in neuroinflammatory conditions is generally considered pathologic, in a murine model of multiple sclerosis, amyloid-forming fibrils, comprised of hexapeptides, are anti-inflammatory. Whether these molecules modulate systemic inflammatory conditions remains unknown. We hypothesized that an amylin hexapeptide that forms fibrils can attenuate the systemic inflammatory response in a murine model of sepsis. To test this hypothesis, mice were pre-treated with either vehicle or amylin hexapeptide (20 μg) at 12 hours and 6 hours prior to intraperitoneal (i.p.) lipopolysaccharide (LPS, 20 mg/kg) administration. Illness severity and survival were monitored every 6 hours for 3 days. Levels of pro- (IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-10) cytokines were measured via ELISA at 1, 3, 6, 12, and 24 hours after LPS (i.p.). As a metric of lung injury, pulmonary artery endothelial cell (PAEC) barrier function was tested 24 hours after LPS administration by comparing lung wet-to-dry ratios, Evan's blue dye (EBD) extravasation, lung histology and caspase-3 activity. Compared to controls, pretreatment with amylin hexapeptide significantly reduced mortality (p<0.05 at 72 h), illness severity (p<0.05), and pro-inflammatory cytokine levels, while IL-10 levels were elevated (p<0.05). Amylin pretreatment attenuated LPS-induced lung injury, as demonstrated by decreased lung water and caspase-3 activity (p<0.05, versus PBS). Hence, in a murine model of systemic inflammation, pretreatment with amylin hexapeptide reduced mortality, disease severity, and preserved lung barrier function. Amylin hexapeptide may represent a novel therapeutic tool to mitigate sepsis severity and lung injury.

  View details for PubMedID 29990318

• Developmental differences in focal adhesion kinase expression modulate pulmonary endothelial barrier function in response to inflammation AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Ying, L., Alvira, C. M., Cornfield, D. N. 2018; 315 (1): L66–L77

  View details for DOI 10.1152/ajplung.00363.2017

  View details for Web of Science ID 000440952000007

• Pediatric pulmonary medicine: at the nexus of care and discovery CURRENT OPINION IN PEDIATRICS Cornfield, D. N. 2018; 30 (3): 364–65

  View details for PubMedID 29553958

• The Effect of Combining Business Training, Microfinance, and Support Group Participation on Economic Status and Intimate Partner Violence in an Unplanned Settlement of Nairobi, Kenya. Journal of interpersonal violence Sarnquist, C. C., Ouma, L., Lang'at, N., Lubanga, C., Sinclair, J., Baiocchi, M. T., Cornfield, D. N. 2018: 886260518779067

  Abstract

  Intimate partner violence (IPV) has myriad negative health and economic consequences for women and families. We hypothesized that empowering women through a combination of formal business training, microfinance, and IPV support groups would decrease IPV and improve women's economic status. The study included adult female survivors of severe IPV. Women living in Korogocho received the intervention and women in Dandora served as a standard of care (SOC) group, but received the intervention at the end of the follow-up period. Women in the intervention groups ( n = 82, SOC group, n = 81) received 8 weeks of business training, assistance creating a business plan, a small initial loan (about US$60), and weekly business and social support meetings. The two primary outcome measures included change in: (a) average daily profit margin, and (b) incidence of severe IPV. Exploratory analysis also looked at incidence of violence against children and women's self-efficacy. Average daily profit margin in the intervention group increased by 351 Kenyan Shillings (about US$3.5) daily (95% CI = [172, 485]). IPV directed against participating women decreased from a baseline of 2.1 to 0.26 incidents, a difference of 1.84 incidents (95% CI = [1.32, 2.36]). Violence against children in the household in the prior 3 months decreased from 1.1 to 0.55 incidents, a difference of 0.55 incidents (95% CI = [0.16, 1.03]). Finally, the intervention appears to have increased self-efficacy scores by 0.42 points (95% CIs 0.13, 0.71). In a low-resource urban environment, employing three complementary interventions resulted in higher daily profit margins and lower IPV in the intervention compared with the SOC group. These data support the notion that employing multiple interventions concomitantly might possess synergistic, beneficial effects, and hold promise to address profound poverty and interrupt the devastating cycle of IPV.

  View details for PubMedID 29862883

• An Amyloidogenic Hexapeptide Derived from Amylin Attenuates Inflammation and Acute Lung Injury in Murine Sepsis Mahapatra, S., Ying, L., Steinman, L., Cornfield, D. AMER ACAD PEDIATRICS. 2018

  View details for DOI 10.1542/peds.142.1_MeetingAbstract.9

  View details for Web of Science ID 000540807300012

• Passive Nocturnal Physiologic Monitoring Enables Early Detection of Exacerbations in Asthmatic Children: A Proof of Concept Study. American journal of respiratory and critical care medicine Huffaker, M. F., Carchia, M., Harris, B. U., Kethman, W. C., Murphy, T. E., Sakarovitch, C. C., Qin, F., Cornfield, D. N. 2018

  Abstract

  RATIONALE: Asthma management depends on prompt identification of symptoms, which challenges both patients and providers. In asthma, a misapprehension of health between exacerbations can compromise compliance. Thus, there is a need for a tool that permits objective longitudinal monitoring without increasing the burden of patient compliance.OBJECTIVES: We sought to determine whether changes in nocturnal physiology are associated with asthma symptoms in pediatric patients.METHODS: Using a contactless bed sensor, nocturnal heart rate, respiratory rate, relative stroke volume, and movement in asthmatic children 5-18 years old (n=16) were recorded. Asthma symptoms and Asthma Control Test score were reported every two weeks. Random forest model was used to identify physiologic parameters associated with asthma symptoms. Elastic net regression was used to identify variables associated with Asthma Control Test score.MEASUREMENTS AND MAIN RESULTS: The model on the full cohort performed with sensitivity of 47.2%, specificity of 96.3%, and accuracy of 87.4%; heart rate and respiratory parameters were the most important variables in this model. The model predicted asthma symptoms 35% of the time on the day prior to perception of symptoms, and 100% of the time for a select subject for which the model performed with greater sensitivity. Multivariable and bivariable analyses demonstrated significant association between heart rate and respiratory rate parameters and Asthma Control Test score.CONCLUSIONS: Nocturnal physiologic changes correlate with asthma symptoms, supporting the notion that nocturnal physiologic monitoring represents an objective diagnostic tool capable longitudinally assessing disease control and predicting asthma exacerbations in asthmatic children at home.

  View details for PubMedID 29688023

• beta1 Subunit of the Calcium-Sensitive Potassium Channel Modulates the Pulmonary Vascular Smooth Muscle Cell Response to Hypoxia. American journal of physiology. Lung cellular and molecular physiology Barnes, E. A., Lee, L., Barnes, S. L., Brenner, R., Alvira, C. M., Cornfield, D. N. 2018

  Abstract

  Accessory subunits associated with the calcium-sensitive potassium channel (BKCa), a major determinant of vascular tone, confer functional and anatomical diversity. The beta1 subunit increases Ca2+-, and voltage-sensitivity of the BKCa channel and is expressed exclusively in smooth muscle cells (SMC). Evidence supporting the physiologic significance of the beta1 subunit includes the observations that murine models with deletion of the beta1 subunit are hypertensive and that humans with a gain-of-function beta1 mutation are at decreased risk of diastolic hypertension, However, whether the beta1 subunit of the BKCa channel contributes to the low tone that characterizes the normal pulmonary circulation or modulates the pulmonary vascular response to hypoxia remains unknown. To determine the role of the BKCa channel beta1 subunit in the regulation of pulmonary vascular tone and the response to acute and chronic hypoxia, mice with deletion of the Kcnmb1 gene that encodes for the beta1 subunit ( Kcnmb1+/+) were placed in chronic hypoxia (10% O2) for 21-24 days. In normoxia, right ventricular systolic pressure (RVSP) did not differ between Kcnmb1+/+ (controls) and Kcnmb1-/- mice. After exposure to either acute or chronic hypoxia, RVSP was higher in Kcnmb1+/+ mice compared to Kcnmb1+/+ mice, without increased vascular remodeling. beta1 subunit expression was predominantly confined to pulmonary artery smooth muscle cells (PASMC) from vessels <150m. Peripheral PASMC contracted collagen gels irrespective of beta1 expression. Focal adhesion expression and Rho kinase activity were greater in Kcnmb1-/- compared to Kcnmb1+/+PASMC. Compromised PASMC beta1 function may contribute to the heightened microvascular vasoconstriction that characterizes pulmonary hypertension.

  View details for PubMedID 29644895

• Developmental Differences in Focal Adhesion Kinase Expression Modulate Pulmonary Endothelial Barrier Function in Response to Inflammation. American journal of physiology. Lung cellular and molecular physiology Ying, L., Alvira, C. M., Cornfield, D. N. 2018

  Abstract

  Compromised pulmonary endothelial cell (PEC) barrier function characterizes acute respiratory distress syndrome (ARDS), a cause of substantial morbidity and mortality. Survival from ARDS is greater in children compared to adults. Whether developmental differences intrinsic to PEC barrier function contribute to this survival advantage remains unknown. To test the hypothesis that PEC barrier function is more well preserved in neonatal compared to adult lungs in response to inflammation, we induced lung injury in neonatal and adult mice with systemic lipopolysaccharide (LPS). We assessed PEC barrier function in vivo and in vitro, evaluated changes in the expression of focal adhesion kinase (FAK1) and phosphorylation in response to LPS, and determined the effect of FAK silencing and over-expression on PEC barrier function. We found that LPS induced a greater increase in lung permeability and PEC barrier disruption in the adult, despite similar degrees of inflammation and apoptosis. Although baseline expression was similar, LPS increased FAK1 expression in neonatal PEC but increased FAK1 phosphorylation and decreased FAK1 expression in adult PEC. Pharmacologic inhibition of FAK1 accentuated LPS-induced barrier disruption most in adult PEC. Finally, in response to LPS, FAK silencing markedly impaired neonatal PEC barrier function, while FAK over-expression preserved adult PEC barrier function. Thus, developmental differences in FAK expression during inflammatory injury serve to preserve neonatal pulmonary endothelial barrier function as compared to adult, and suggest that intrinsic differences in the immature versus pulmonary endothelium, especially relative to FAK1 phosphorylation, may contribute to the improved outcomes of children with ARDS.

  View details for PubMedID 29597831

• TRPV4 Promotes Myometrial Inflammation and Contractility in Preterm Mice Exposed to Low Dose Lipopolysaccharide. Rodriguez, Z., Ying, L., Cornfield, D. N., Alvira, C. M. SAGE PUBLICATIONS INC. 2018: 190A

  View details for Web of Science ID 000429928200405

• In Status Asthmaticus, Changes in Heart and Respiratory Rates Have Important Prognostic Implications Okorie, C., Balasubramanian, V., Sakarovitch, C., Hedlin, H., Harris, B., Kethman, W. C., Huffaker, M., Cornfield, D. N. AMER THORACIC SOC. 2018

  View details for Web of Science ID 000449978901431

• The evolution of disease: chronic lung disease of infancy and pulmonary hypertension CURRENT OPINION IN PEDIATRICS Tracy, M. C., Cornfield, D. N. 2017; 29 (3): 320-325

  Abstract

  Bronchopulmonary dysplasia (BPD) or chronic lung disease of infancy BPD was originally described 50 years ago, in 1967 by Northway et al. This article possesses two fundamental objectives to provide: a brief historical perspective on BPD; and an update relative to current notions of epidemiology, pathophysiology, evaluation, and clinical management of BPD complicated by vascular disease. The review highlights areas of consensus and ongoing uncertainty.The clinical cause and presentation of infants with BPD has evolved over the past several decades. Considerable improvements in neonatal care, including surfactant replacement therapies, antenatal steroids, nutritional support, ventilator management, and attention to the potential of oxygen toxicity, underlie the evolution of BPD. Most children with BPD improve over time. However, in the presence of vascular disease, the morbidity and mortality associated with BPD increases considerably. Though recent recommendations include procuring an echocardiogram to screen for pulmonary hypertension in infants with established BPD, there is less agreement surrounding the additional diagnostic and putative treatment modalities for infants with BPD and pulmonary hypertension. The indications, rationale, potential benefits, and risks of vasodilator therapy in BPD are discussed.The pediatric community has 50 years of experience with BPD. Past experience should be used to inform present and future diagnostic and treatment strategies. This review seeks to arm the clinician with evidence that motivates a physiology-based approach to the management of infants with BPD and pulmonary hypertension.

  View details for DOI 10.1097/MOP.0000000000000490

  View details for Web of Science ID 000401074000011

  View details for PubMedID 28338487

• Pediatric pulmonary medicine, then and next CURRENT OPINION IN PEDIATRICS Cornfield, D. N. 2017; 29 (3): 303–4

  View details for PubMedID 28338489

• the Only Question. Hospital pediatrics Tracy, M. C., Cornfield, D. N. 2017; 7 (5): 297-299

  View details for DOI 10.1542/hpeds.2017-0047

  View details for PubMedID 28424244

• Disrupted BKCa Channel beta 1 Subunit Gene Contributes to Vascular Dysfunction in Pulmonary Hypertension Barnes, E. A., Chen, C., Lee, L., Barnes, S. L., Cornfield, D. N. FEDERATION AMER SOC EXP BIOL. 2017

  View details for Web of Science ID 000405461402450

• Micro-RNA 203 Regulates Myometrial Smooth Muscle Cell Expression of the Transient Receptor Vanilloid 4 Channel Ying, L., Barnes, E. A., Rodriguez, S., Alvira, C. M., Cornfield, D. N. FEDERATION AMER SOC EXP BIOL. 2017

  View details for Web of Science ID 000405461403418

• Loss of smooth muscle cell hypoxia inducible factor-1 alpha underlies increased vascular contractility in pulmonary hypertension FASEB JOURNAL Barnes, E. A., Chen, C., Sedan, O., Cornfield, D. N. 2017; 31 (2): 650-662

  Abstract

  Pulmonary arterial hypertension (PAH) is an often fatal disease with limited treatment options. Whereas current data support the notion that, in pulmonary artery endothelial cells (PAECs), expression of transcription factor hypoxia inducible factor-1α (HIF-1α) is increased, the role of HIF-1α in pulmonary artery smooth muscle cells (PASMCs) remains controversial. This study investigates the hypothesis that, in PASMCs from patients with PAH, decreases in HIF-1α expression and activity underlie augmented pulmonary vascular contractility. PASMCs and tissues were isolated from nonhypertensive controls and patients with PAH. Compared with controls, HIF-1α and Kv1.5 protein expression were decreased in PAH smooth muscle cells (primary culture). Myosin light chain (MLC) phosphorylation and MLC kinase (MLCK) activity-major determinants of vascular tone-were increased in patients with PAH. Cofactors involved in prolyl hydroxylase domain activity were increased in PAH smooth muscle cells. Functionally, PASMC contractility was inversely correlated with HIF-1α activity. In PASMCs derived from patients with PAH, HIF-1α expression is decreased, and MLCK activity, MLC phosphorylation, and cell contraction are increased. We conclude that compromised PASMC HIF-1α expression may contribute to the increased tone that characterizes pulmonary hypertension.-Barnes, E. A., Chen, C.-H., Sedan, O., Cornfield, D. N. Loss of smooth muscle cell hypoxia inducible factor-1α underlies increased vascular contractility in pulmonary hypertension.

  View details for DOI 10.1096/fj.201600557R

  View details for Web of Science ID 000394235400018

• Hypoxia Inducible Factor-1 alpha Increases Bone Morphogenetic Protein Receptor 2 Signaling In Pulmonary Artery Endothelial Cells (paecs) Kuang, J., Tian, X., Prosseda, S., Tian, A., Cornfield, D., Nicolls, M. R., Spiekerkoetter, E. F. AMER THORACIC SOC. 2017

  View details for Web of Science ID 000400372501417

• Unique aspects of the developing lung circulation: structural development and regulation of vasomotor tone PULMONARY CIRCULATION Gao, Y., Cornfield, D. N., Stenmark, K. R., Thebaud, B., Abman, S. H., Raj, J. U. 2016; 6 (4): 407-425

  Abstract

  This review summarizes our current knowledge on lung vasculogenesis and angiogenesis during normal lung development and the regulation of fetal and postnatal pulmonary vascular tone. In comparison to that of the adult, the pulmonary circulation of the fetus and newborn displays many unique characteristics. Moreover, altered development of pulmonary vasculature plays a more prominent role in compromised pulmonary vasoreactivity than in the adult. Clinically, a better understanding of the developmental changes in pulmonary vasculature and vasomotor tone and the mechanisms that are disrupted in disease states can lead to the development of new therapies for lung diseases characterized by impaired alveolar structure and pulmonary hypertension.

  View details for DOI 10.1086/688890

  View details for Web of Science ID 000389303800002

  View details for PubMedID 27942377

  View details for PubMedCentralID PMC5130074

• Loss of smooth muscle cell hypoxia inducible factor-1a underlies increased vascular contractility in pulmonary hypertension. FASEB journal Barnes, E. A., Chen, C., Sedan, O., Cornfield, D. N. 2016

  Abstract

  Pulmonary arterial hypertension (PAH) is an often fatal disease with limited treatment options. Whereas current data support the notion that, in pulmonary artery endothelial cells (PAECs), expression of transcription factor hypoxia inducible factor-1α (HIF-1α) is increased, the role of HIF-1α in pulmonary artery smooth muscle cells (PASMCs) remains controversial. This study investigates the hypothesis that, in PASMCs from patients with PAH, decreases in HIF-1α expression and activity underlie augmented pulmonary vascular contractility. PASMCs and tissues were isolated from nonhypertensive controls and patients with PAH. Compared with controls, HIF-1α and Kv1.5 protein expression were decreased in PAH smooth muscle cells (primary culture). Myosin light chain (MLC) phosphorylation and MLC kinase (MLCK) activity-major determinants of vascular tone-were increased in patients with PAH. Cofactors involved in prolyl hydroxylase domain activity were increased in PAH smooth muscle cells. Functionally, PASMC contractility was inversely correlated with HIF-1α activity. In PASMCs derived from patients with PAH, HIF-1α expression is decreased, and MLCK activity, MLC phosphorylation, and cell contraction are increased. We conclude that compromised PASMC HIF-1α expression may contribute to the increased tone that characterizes pulmonary hypertension.-Barnes, E. A., Chen, C.-H., Sedan, O., Cornfield, D. N. Loss of smooth muscle cell hypoxia inducible factor-1α underlies increased vascular contractility in pulmonary hypertension.

  View details for PubMedID 27811062

• There Is No "I" in Team: New Challenges for Career Development in the Era of Team Science JOURNAL OF PEDIATRICS Libby, A. M., Cornfield, D. N., Abman, S. H. 2016; 177: 4–5

  View details for PubMedID 27473883

• Hypoxia-inducible factor-1 plays a role in phosphate-induced vascular smooth muscle cell calcification KIDNEY INTERNATIONAL Mokas, S., Lariviere, R., Lamalice, L., Gobeil, S., Cornfield, D. N., Agharazii, M., Richard, D. E. 2016; 90 (3): 598-609

  Abstract

  Medial vascular calcification is a common complication of chronic kidney disease (CKD). Although elevated inorganic phosphate stimulates vascular smooth muscle cell (VSMC) osteogenic transdifferentiation and calcification, the mechanisms involved in their calcification during CKD are not fully defined. Because hypoxic gene activation is linked to CKD and stimulates bone cell osteogenic differentiation, we used in vivo and in vitro rodent models to define the role of hypoxic signaling during elevated inorganic phosphate-induced VSMC calcification. Cell mineralization studies showed that elevated inorganic phosphate rapidly induced VSMC calcification. Hypoxia strongly enhanced elevated inorganic phosphate-induced VSMC calcification and osteogenic transdifferentiation, as seen by osteogenic marker expression. Hypoxia-inducible factor-1 (HIF-1), the key hypoxic transcription factor, was essential for enhanced VSMC calcification. Targeting HIF-1 expression in murine VSMC blocked calcification in hypoxia with elevated inorganic phosphate while HIF-1 activators, including clinically used FG-4592/Roxadustat, recreated a procalcifying environment. Elevated inorganic phosphate rapidly activated HIF-1, even in normal oxygenation; an effect mediated by HIF-1α subunit stabilization. Thus, hypoxia synergizes with elevated inorganic phosphate to enhance VSMC osteogenic transdifferentiation. Our work identifies HIF-1 as an early CKD-related pathological event, prospective marker, and potential target against vascular calcification in CKD-relevant conditions.

  View details for DOI 10.1016/j.kint.2016.05.020

  View details for Web of Science ID 000382415300019

  View details for PubMedID 27470678

• Pulmonary hypertension in the premature infant: a challenging comorbidity in a vulnerable population CURRENT OPINION IN PEDIATRICS O'Connor, M. G., Cornfield, D. N., Austin, E. D. 2016; 28 (3): 324-330

  Abstract

  This review is written from the perspective of the pediatric clinician involved in the care of premature infants at risk for pulmonary hypertension. The main objective is to better inform the clinician in the diagnosis and treatment of pulmonary hypertension in premature infants by reviewing the available relevant literature and focusing on the areas for which there is the greatest need for continued research.Continued knowledge regarding the epidemiology of pulmonary hypertension in the premature infant population has aided better diagnostic screening algorithms. Included in this knowledge, is the association of pulmonary hypertension in infants with bronchopulmonary dysplasia (BPD). However, it is also known that beyond BPD, low birth weight and other conditions that result in increased systemic inflammation are associated with pulmonary hypertension. This information has led to the recent recommendation that all infants with BPD should have an echocardiogram to evaluate for evidence of pulmonary hypertension prior to discharge from the neonatal ICU.Pulmonary hypertension can be a significant comorbidity for premature infants. This review aims to focus the clinician on the available literature to improve recognition of the condition to allow for more timely interventions.

  View details for DOI 10.1097/MOP.0000000000000355

  View details for PubMedID 27043088

• Pediatric pulmonology: with thin phenotyping and deep genotyping, knowledge is power CURRENT OPINION IN PEDIATRICS Cornfield, D. N. 2016; 28 (3): 310–11

  View details for PubMedID 27093355

• KCNMB1(-/-) Mice as a Model of Pulmonary Arterial Hypertension Barnes, E., Chen, C., Barnes, S., Kim, F., Lee, L., Alvira, C., Cornfield, D. FEDERATION AMER SOC EXP BIOL. 2016

  View details for Web of Science ID 000406444006555

• A Role for the Transient Receptor Potential Vanilloid 4 Channel in Modulating Uterine Tone During Pregnancy Ying, L., Alvira, C. M., Cornfield, D. N. FEDERATION AMER SOC EXP BIOL. 2016

  View details for Web of Science ID 000406444705552

• KCNMB1(-/-) Mice as a Model of Pulmonary Arterial Hypertension Barnes, E., Chen, C., Barnes, S., Kim, F., Lee, L., Alvira, C., Cornfield, D. FEDERATION AMER SOC EXP BIOL. 2016

  View details for Web of Science ID 000406444001556

• Diagnostic Dilemma in the Treatment of a Fatal Case of Bloody Diarrhea. Journal of investigative medicine high impact case reports Mahapatra, S., Michie, S. A., Sylvester, K., Cornfield, D. 2016; 4 (1): 2324709616638698-?

  Abstract

  Although diarrhea is the most commonly reported pediatric illness in the United States, mortality is usually a rare and unexpected event. We report the case of a healthy 13-month-old male that succumbed to a diarrheal illness of unclear etiology. Presenting signs included frequent nonbloody stools that progressed to frankly bloody stools over 72 hours. Associated symptoms included fever, tenesmus, relief with stool passage, and significant fatigue. On examination, the patient appeared tired and lay with legs curled toward his chest. The abdominal exam was remarkable for hypoactive bowel sounds, diffuse tenderness to palpation without guarding or rebound pain, and intermittent prolapse of rectal tissue. Abdominal plain films demonstrated a paucity of bowel gas, especially in the rectum; and ultrasound revealed thickening of bowel loops in the left lower quadrant. Abdominal computed tomography scan showed decreased enhancement of the mucosa of the rectosigmoid colon. The patient deteriorated rapidly with cardiorespiratory arrest occurring 48 hours after admission. Despite a protracted effort at cardiopulmonary resuscitation, perfusing heart rate or rhythm could not be reestablished. Autopsy revealed infarction and necrosis of the rectosigmoid colon with invasive gram-negative bacilli. Here we present his perplexing case, diagnostic evaluations, and suggest a unifying diagnosis.

  View details for DOI 10.1177/2324709616638698

  View details for PubMedID 27069937

  View details for PubMedCentralID PMC4811016

• Longitudinal Automated Airway And Air-Trapping Analysis On CT In School Age Children With Mild Cystic Fibrosis Lung Disease Wielpuetz, M. O., Robinson, T. E., Konietzke, P., Heussel, C., Kauczor, H., Galban, C., Cornfield, D. N., Savage, D., Newman, B., Weinheimer, O. AMER THORACIC SOC. 2016

  View details for Web of Science ID 000390749604095

• In Patients With Pulmonary Arterial Hypertension, Pulmonary Artery Smooth Muscle Cell Hypoxia Inducible Factor-1 alpha Expression And Activity Is Decreased Barnes, E. A., Chen, C., Sedan, O., Cornfield, D. N. AMER THORACIC SOC. 2016

  View details for Web of Science ID 000390749601348

• Respiratory Microbiology In Primary Ciliary Dyskinesia: Comparisons To A Pediatric Cystic Fibrosis Cohort Tracy, M. C., Zirbes, J. M., Hernandez, C., Cornfield, D. N., Milla, C. E. AMER THORACIC SOC. 2016

  View details for Web of Science ID 000390749606226

• Dna Extraction From Cystic Fibrosis Sputum Samples Is Not Method Dependent Tracy, M. C., Yacob, A., Chen, C., Milla, C. E., Cornfield, D. N. AMER THORACIC SOC. 2016

  View details for Web of Science ID 000390749600791

• Shifting the Paradigm in Hemolytic Uremic Syndrome PEDIATRICS Cornfield, D. N. 2016; 137 (1)

  View details for PubMedID 26644489

  View details for PubMedCentralID PMC4702026

• The transient receptor potential vanilloid 4 channel modulates uterine tone during pregnancy SCIENCE TRANSLATIONAL MEDICINE Ying, L., Becard, M., Lyell, D., Han, X., Shortliffe, L., Husted, C. I., Alvira, C. M., Cornfield, D. N. 2015; 7 (319)

  Abstract

  The importance of gaining insight into the mechanisms underlying uterine quiescence and contractility is highlighted by the absence of an effective strategy to prevent or treat preterm labor, the greatest cause of perinatal mortality and morbidity worldwide. Although current evidence suggests that in myometrial smooth muscle cells (mSMCs) calcium homeostasis is modulated near term to promote uterine contractility, the efficacy of blocking voltage-operated calcium channels is limited by dose-related cardiovascular side effects. Thus, we considered whether uterine contractility might be modulated by calcium entry via transient receptor potential vanilloid 4 (TRPV4) channels. In mSMC, TRPV4 gene and protein expression increased with gestation, and TRPV4-mediated Ca(2+) entry and contractility were increased in mSMC from pregnant compared to nonpregnant rats. Cell membrane TRPV4 expression was specifically increased, whereas the expression of β-arrestin-1 and β-arrestin-2, molecules that can sequester TRPV4 in the cytoplasm, decreased. Physical interaction of β-arrestin-2 and TRPV4 was apparent in nonpregnant, but absent in pregnant, mouse uterus. Moreover, direct pharmacologic activation of TRPV4 increased uterine contraction, but oxytocin-induced myometrial contraction was blocked by pharmacologic inhibition of TRPV4 and decreased in mice with global deletion of TRPV4. Finally, TRPV4 channel blockade prolonged pregnancy in two distinct in vivo murine models of preterm labor, whereas the absence of either β-arrestin-1 or β-arrestin-2 increased susceptibility to preterm labor. These data suggest that TRPV4 channel activity modulates uterine contractility and might represent a therapeutic target to address preterm labor.

  View details for DOI 10.1126/scitranslmed.aad0376

  View details for PubMedID 26702092

• Pediatric Pulmonary Hypertension Guidelines From the American Heart Association and American Thoracic Society CIRCULATION Abman, S. H., Hansmann, G., Archer, S. L., Ivy, D. D., Adatia, I., Chung, W. K., Hanna, B. D., Rosenzweig, E. B., Raj, J. U., Cornfield, D., Stenmark, K. R., Steinhorn, R., Theobaud, B., Fineman, J. R., Kuehne, T., Feinstein, J. A., Friedberg, M. K., Earing, M., Barst, R. J., Keller, R. L., Kinsella, J. P., Mullen, M., Deterding, R., Kulik, T., Mallory, G., Humpl, T., Wessel, D. L. 2015; 132 (21): 2037-2099

  Abstract

  Pulmonary hypertension is associated with diverse cardiac, pulmonary, and systemic diseases in neonates, infants, and older children and contributes to significant morbidity and mortality. However, current approaches to caring for pediatric patients with pulmonary hypertension have been limited by the lack of consensus guidelines from experts in the field. In a joint effort from the American Heart Association and American Thoracic Society, a panel of experienced clinicians and clinician-scientists was assembled to review the current literature and to make recommendations on the diagnosis, evaluation, and treatment of pediatric pulmonary hypertension. This publication presents the results of extensive literature reviews, discussions, and formal scoring of recommendations for the care of children with pulmonary hypertension.

  View details for DOI 10.1161/CIR.0000000000000329

  View details for Web of Science ID 000365574600015

  View details for PubMedID 26534956

• Noninvasive monitoring of infection and rejection after lung transplantation. Proceedings of the National Academy of Sciences of the United States of America De Vlaminck, I., Martin, L., Kertesz, M., Patel, K., Kowarsky, M., Strehl, C., Cohen, G., Luikart, H., Neff, N. F., Okamoto, J., Nicolls, M. R., Cornfield, D., Weill, D., Valantine, H., Khush, K. K., Quake, S. R. 2015; 112 (43): 13336-13341

  Abstract

  The survival rate following lung transplantation is among the lowest of all solid-organ transplants, and current diagnostic tests often fail to distinguish between infection and rejection, the two primary posttransplant clinical complications. We describe a diagnostic assay that simultaneously monitors for rejection and infection in lung transplant recipients by sequencing of cell-free DNA (cfDNA) in plasma. We determined that the levels of donor-derived cfDNA directly correlate with the results of invasive tests of rejection (area under the curve 0.9). We also analyzed the nonhuman cfDNA as a hypothesis-free approach to test for infections. Cytomegalovirus is most frequently assayed clinically, and the levels of CMV-derived sequences in cfDNA are consistent with clinical results. We furthermore show that hypothesis-free monitoring for pathogens using cfDNA reveals undiagnosed cases of infection, and that certain infectious pathogens such as human herpesvirus (HHV) 6, HHV-7, and adenovirus, which are not often tested clinically, occur with high frequency in this cohort.

  View details for DOI 10.1073/pnas.1517494112

  View details for PubMedID 26460048

• Inhaled ß2-Agonist Therapy Increases Functional Residual Capacity in Mechanically Ventilated Children With Respiratory Failure. Pediatric critical care medicine Ramsi, M. A., Henry, M., Milla, C. E., Cornfield, D. N. 2015; 16 (7): e189-93

  Abstract

  To test the hypothesis that in mechanically ventilated children with respiratory failure, aerosolized albuterol modifies functional residual capacity, lung mechanics, oxygen consumption, and hemodynamics.Prospective, self-control clinical trial.A 24-bed PICU in a quaternary care, academic children's hospital.25 children (age range, 1-18 yr) undergoing mechanical ventilation to treat respiratory failure. Entry criteria included previously prescribed inhaled β2 agonists. Physiologic measurements were performed prior to and 20 minutes after administration of aerosolized albuterol solution. Functional residual capacity was determined via nitrogen washout.Functional residual capacity, oxygen consumption, respiratory mechanics, and vital signs were measured were measured prior to and 20 minutes after administration of aerosolized albuterol solution. Functional residual capacity was determined via nitrogen washout.At baseline, functional residual capacity is only 53% of predicted. After aerosolized albuterol, functional residual capacity increased by 18.3% (p = 0.008). Overall, aerosolized albuterol had no effect on airway resistance. However, in patients with an endotracheal tube size of more than or equal to 4.0 mm, resistance decreased from 33 ± 3 to 25 ± 3 (p < 0.02). Inhaled albuterol administration had no effect on oxygen consumption despite an increase in heart rate from 116 ± 2 to 128 ± 2 beats/min (p < 0.0001).In pediatric patients with respiratory failure, aerosolized albuterol increases functional residual capacity without a decrease in resistance. In infants and children, aerosolized albuterol might favorably enhance pulmonary mechanics and thereby represent a novel strategy for lung recruitment in children with respiratory failure.

  View details for DOI 10.1097/PCC.0000000000000448

  View details for PubMedID 25901546

• Sleep medicine: pediatric polysomnography revisited CURRENT OPINION IN PEDIATRICS Cornfield, D. N., Bhargava, S. 2015; 27 (3): 325-328

  Abstract

  Sleep medicine is an increasingly well subscribed component of pediatric medicine. While knowledge has increased significantly in the past five decades, whether the most widely used tool to assess sleep-disordered breathing possesses demonstrable clinical utility remains unknown. The absence of certainty surrounding the impact of polysomnography (PSG) testing on clinical outcomes, superimposed on the cost and inconvenience of PSG testing, prompts a call to reassess the current normative stance toward PSG testing.The present study argues for the use of the following: endpoints that have known clinical significance; readily available data provided by parents; and data derived from a randomized, placebo-controlled trial to determine the merits of PSG testing in the context of obstructive sleep apnea.By rationalizing the use PSG testing, cost, inconvenience, and parental anxiety can be decreased without compromising care.

  View details for DOI 10.1097/MOP.0000000000000219

  View details for Web of Science ID 000354214800010

  View details for PubMedID 25944311

• Progress in pediatric pulmonary medicine: incremental and exponential CURRENT OPINION IN PEDIATRICS Cornfield, D. N. 2015; 27 (3): 315–16

  View details for PubMedID 25944314

• Non-Invasive Monitoring of Infection and Rejection After Lung Transplantation Vlaminck, I. D., Martin, L., Kertesz, M., Patel, K. N., Kowarsky, M., Strehl, C., Cohen, G., Luikart, H., Neff, N., Okamoto, J., Nicolls, M. N., Cornfield, D. N., Weill, D., Valantine, H. A., Khush, K. K., Quake, S. R. ELSEVIER SCIENCE INC. 2015: S137

  View details for DOI 10.1016/j.healun.2015.01.368

  View details for Web of Science ID 000353251500348

• Differential Focal Adhesion Kinase (FAK) Expression Accounts for the Developmental Regulation of Pulmonary Artery Endothelial Cell(PAEC) Barrier Function Ying, L., Barnes, E., Alvira, C., Cornfield, D. FEDERATION AMER SOC EXP BIOL. 2015

  View details for Web of Science ID 000361470506125

• HIF-1 alpha Expression is Decreased and Contractility is Enhanced in PASMC from PAH Patients Barnes, E., Chen, C., Alvira, C., Cornfield, D. FEDERATION AMER SOC EXP BIOL. 2015

  View details for Web of Science ID 000361470506141

• Pulmonary artery smooth muscle cell endothelin-1 expression modulates the pulmonary vascular response to chronic hypoxia. American journal of physiology. Lung cellular and molecular physiology Kim, F. Y., Barnes, E. A., Ying, L., Chen, C., Lee, L., Alvira, C. M., Cornfield, D. N. 2015; 308 (4): L368-77

  Abstract

  Endothelin-1 (ET-1) increases pulmonary vascular tone through direct effects on pulmonary artery smooth muscle cells (PASMC) via membrane-bound ET-1 receptors. Circulating ET-1 contributes to vascular remodeling by promoting SMC proliferation and migration and inhibiting SMC apoptosis. Although endothelial cells (EC) are the primary source of ET-1, whether ET-1 produced by SMC modulates pulmonary vascular tone is unknown. Using transgenic mice created by crossbreeding SM22α-Cre mice with ET-1(flox/flox) mice to selectively delete ET-1 in SMC, we tested the hypothesis that PASMC ET-1 gene expression modulates the pulmonary vascular response to hypoxia. ET-1 gene deletion and selective activity of SM22α promoter-driven Cre recombinase were confirmed. Functional assays were performed under normoxic (21% O2) or hypoxic (5% O2) conditions using murine PASMC obtained from ET-1(+/+) and ET-1(-/-) mic and in human PASMC (hPASMC) after silencing of ET-1 using siRNA. Under baseline conditions, there was no difference in right ventricular systolic pressure (RVSP) between SM22α-ET-1(-/-) and SM22α-ET-1(+/+) (control) littermates. After exposure to hypoxia (10% O2, 21-24 days), RVSP was and vascular remodeling were less in SM22α-ET-1(-/-) mice compared with control littermates (P < 0.01). Loss of ET-1 decreased PASMC proliferation and migration and increased apoptosis under normoxic and hypoxic conditions. Exposure to selective ET-1 receptor antagonists had no effect on either the hypoxia-induced hPASMC proliferative or migratory response. SMC-specific ET-1 deletion attenuates hypoxia-induced increases in pulmonary vascular tone and structural remodeling. The observation that loss of ET-1 inhibited SMC proliferation, survival, and migration represents evidence that ET-1 derived from SMC plays a previously undescribed role in modulating the response of the pulmonary circulation to hypoxia. Thus PASMC ET-1 may modulate vascular tone independently of ET-1 produced by EC.

  View details for DOI 10.1152/ajplung.00253.2014

  View details for PubMedID 25399435

• Pulmonary artery smooth muscle cell endothelin-1 expression modulates the pulmonary vascular response to chronic hypoxia AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Kim, F. Y., Barnes, E. A., Ying, L., Chen, C., Lee, L., Alvira, C. M., Cornfield, D. N. 2015; 308 (4): L368-L377

  View details for DOI 10.1152/ajplung.00253.2014

  View details for Web of Science ID 000349305400006

  View details for PubMedID 25399435

• Patching the Pipeline: Creation and Retention of the Next Generation of Physician-Scientists for Child Health Research JOURNAL OF PEDIATRICS Cornfield, D. N., Lane, R., Rosenblum, N. D., Hostetter, M., Jobe, A., Albertine, K., Aschner, J., Abman, S. H. 2014; 165 (5): 882–U303

  View details for PubMedID 25441382

• Pediatric lung transplantation: promise being realized. Current opinion in pediatrics Conrad, C., Cornfield, D. N. 2014; 26 (3): 334-342

  Abstract

  Lung transplantation for infants and children is an accepted but rarely exercised option for the treatment of end-stage lung disease, with outcomes equivalent to those for adults. However, widespread misconceptions regarding pediatric outcomes often confound timely and appropriate referral to specialty centers. We present the updated information for primary pediatricians to utilize when counseling families with children confronted by progressive end-stage pulmonary or cardiovascular disease.We provide general guidelines to consider for referral, and discuss allocation of organs in children, information regarding standard treatment protocols, and survival outcomes.Lung transplantation is a worthwhile treatment option to consider in children with end-stage lung disease. The treatment is complex, but lung transplant provides substantial survival benefit and markedly improved quality of life for children and their families. This timely review provides comprehensive information for pediatricians who are considering options for treatment of children with end-stage lung disease.

  View details for DOI 10.1097/MOP.0000000000000085

  View details for PubMedID 24732565

• Pediatric pulmonary medicine: progress at the intersections CURRENT OPINION IN PEDIATRICS Cornfield, D. N. 2014; 26 (3): 304–5

  View details for PubMedID 24759230

• Rape Prevention Through Empowerment of Adolescent Girls PEDIATRICS Sarnquist, C., Omondi, B., Sinclair, J., Gitau, C., Paiva, L., Mulinge, M., Cornfield, D. N., Maldonado, Y. 2014; 133 (5): E1226-E1232

  Abstract

  Sexual assault is a major cause of injury, unplanned pregnancy, HIV infection, and mental health problems worldwide. In parts of sub-Saharan Africa, sexual assault has reached epidemic proportions. This study evaluated the efficacy of an empowerment and self-defense intervention for adolescent girls to decrease the incidence of sexual assault and harassment in Nairobi's large informal settlements.A prospective cohort of 1978 adolescents from 4 neighborhoods near Nairobi were taught empowerment, deescalation, and self-defense skills in six 2-hour sessions. The standard-of-care (SOC) group (n = 428) received a life skills class. Self-reported, anonymous survey data were collected at baseline and 10.5 months after intervention.Annual sexual assault rates decreased from 17.9/100 person-years at baseline to 11.1 at follow-up (rate ratio = 1.61; 95% confidence interval [CI], 1.26-1.86; P < .001); there was no significant change in the SOC group (14.3 to 14.0, rate ratio = 1.02; 95% CI, 0.67-1.57, P = .92). Sexual assault disclosure in the intervention group increased from 56% to 75% (P = .006), compared with a constant incidence of disclosure (53%) in the SOC group. The majority (52.3%) of adolescents in the intervention group reported using skills learned to stop an assault.This intervention decreased sexual assault rates among adolescent girls in Kenya. The intervention was also associated with an increase in the disclosure of assaults, thereby enabling survivors to seek care and support and possibly leading to the identification and prosecution of perpetrators. This model should be adaptable to other settings both in Africa and globally.

  View details for DOI 10.1542/peds.2013-3414

  View details for Web of Science ID 000335236800043

• Rape prevention through empowerment of adolescent girls. Pediatrics Sarnquist, C., Omondi, B., Sinclair, J., Gitau, C., Paiva, L., Mulinge, M., Cornfield, D. N., Maldonado, Y. 2014; 133 (5): e1226-32

  Abstract

  Sexual assault is a major cause of injury, unplanned pregnancy, HIV infection, and mental health problems worldwide. In parts of sub-Saharan Africa, sexual assault has reached epidemic proportions. This study evaluated the efficacy of an empowerment and self-defense intervention for adolescent girls to decrease the incidence of sexual assault and harassment in Nairobi's large informal settlements.A prospective cohort of 1978 adolescents from 4 neighborhoods near Nairobi were taught empowerment, deescalation, and self-defense skills in six 2-hour sessions. The standard-of-care (SOC) group (n = 428) received a life skills class. Self-reported, anonymous survey data were collected at baseline and 10.5 months after intervention.Annual sexual assault rates decreased from 17.9/100 person-years at baseline to 11.1 at follow-up (rate ratio = 1.61; 95% confidence interval [CI], 1.26-1.86; P < .001); there was no significant change in the SOC group (14.3 to 14.0, rate ratio = 1.02; 95% CI, 0.67-1.57, P = .92). Sexual assault disclosure in the intervention group increased from 56% to 75% (P = .006), compared with a constant incidence of disclosure (53%) in the SOC group. The majority (52.3%) of adolescents in the intervention group reported using skills learned to stop an assault.This intervention decreased sexual assault rates among adolescent girls in Kenya. The intervention was also associated with an increase in the disclosure of assaults, thereby enabling survivors to seek care and support and possibly leading to the identification and prosecution of perpetrators. This model should be adaptable to other settings both in Africa and globally.

  View details for DOI 10.1542/peds.2013-3414

  View details for PubMedID 24733880

• Use of electronic medical record-enhanced checklist and electronic dashboard to decrease CLABSIs. Pediatrics Pageler, N. M., Longhurst, C. A., Wood, M., Cornfield, D. N., Suermondt, J., Sharek, P. J., Franzon, D. 2014; 133 (3): e738-46

  Abstract

  We hypothesized that a checklist enhanced by the electronic medical record and a unit-wide dashboard would improve compliance with an evidence-based, pediatric-specific catheter care bundle and decrease central line-associated bloodstream infections (CLABSI).We performed a cohort study with historical controls that included all patients with a central venous catheter in a 24-bed PICU in an academic children's hospital. Postintervention CLABSI rates, compliance with bundle elements, and staff perceptions of communication were evaluated and compared with preintervention data.CLABSI rates decreased from 2.6 CLABSIs per 1000 line-days before intervention to 0.7 CLABSIs per 1000 line-days after intervention. Analysis of specific bundle elements demonstrated increased daily documentation of line necessity from 30% to 73% (P < .001), increased compliance with dressing changes from 87% to 90% (P = .003), increased compliance with cap changes from 87% to 93% (P < .001), increased compliance with port needle changes from 69% to 95% (P < .001), but decreased compliance with insertion bundle documentation from 67% to 62% (P = .001). Changes in the care plan were made during review of the electronic medical record checklist on 39% of patient rounds episodes.Use of an electronic medical record-enhanced CLABSI prevention checklist coupled with a unit-wide real-time display of adherence was associated with increased compliance with evidence-based catheter care and sustained decrease in CLABSI rates. These data underscore the potential for computerized interventions to promote compliance with proven best practices and prevent patient harm.

  View details for DOI 10.1542/peds.2013-2249

  View details for PubMedID 24567021

• Use of Electronic Medical Record-Enhanced Checklist and Electronic Dashboard to Decrease CLABSIs. Pediatrics Pageler, N. M., Longhurst, C. A., Wood, M., Cornfield, D. N., Suermondt, J., Sharek, P. J., Franzon, D. 2014; 133 (3): e738-46

  Abstract

  We hypothesized that a checklist enhanced by the electronic medical record and a unit-wide dashboard would improve compliance with an evidence-based, pediatric-specific catheter care bundle and decrease central line-associated bloodstream infections (CLABSI).We performed a cohort study with historical controls that included all patients with a central venous catheter in a 24-bed PICU in an academic children's hospital. Postintervention CLABSI rates, compliance with bundle elements, and staff perceptions of communication were evaluated and compared with preintervention data.CLABSI rates decreased from 2.6 CLABSIs per 1000 line-days before intervention to 0.7 CLABSIs per 1000 line-days after intervention. Analysis of specific bundle elements demonstrated increased daily documentation of line necessity from 30% to 73% (P < .001), increased compliance with dressing changes from 87% to 90% (P = .003), increased compliance with cap changes from 87% to 93% (P < .001), increased compliance with port needle changes from 69% to 95% (P < .001), but decreased compliance with insertion bundle documentation from 67% to 62% (P = .001). Changes in the care plan were made during review of the electronic medical record checklist on 39% of patient rounds episodes.Use of an electronic medical record-enhanced CLABSI prevention checklist coupled with a unit-wide real-time display of adherence was associated with increased compliance with evidence-based catheter care and sustained decrease in CLABSI rates. These data underscore the potential for computerized interventions to promote compliance with proven best practices and prevent patient harm.

  View details for DOI 10.1542/peds.2013-2249

  View details for PubMedID 24567021

• Haemophagocytic lymphohistiocytosis associated with coccidiomycosis. BMJ case reports Ramsi, M., Alvira, C., Purohit, P., Cornfield, D. 2014; 2014

  Abstract

  Haemophagocytic lymphohistiocytosis (HLH) is a rapidly fatal disease caused by dysregulated histiocytes leading to an excessive inflammatory reaction. While genetic forms of HLH exist, the most common form is acquired, frequently associated with infection. Here we report the first case of HLH associated with a coccidiomycosis infection. This patient is a 13-year-old previously healthy boy who presented with a flu-like illness, which rapidly progressed to refractory shock, severe ARDS, multiorgan failure and death despite maximal medical therapy, including broad-spectrum antibiotics to treat well-established causes of acquired HLH. Autopsy findings revealed the diagnosis of HLH in the setting of pulmonary coccidiomycosis. Antifungal therapy should be considered in cases of acquired HLH when the underlying aetiology is not clear.

  View details for DOI 10.1136/bcr-2014-205681

  View details for PubMedID 25139924

• Hif-1 alpha Expression Is Decreased In Pulmonary Artery Smooth Muscle Cells From Patients With Pulmonary Arterial Hypertension Barnes, E. A., Lee, L., Chen, C., Alvira, C. M., Cornfield, D. N. AMER THORACIC SOC. 2014

  View details for Web of Science ID 000209838204308

• Temporal response of the human virome to immunosuppression and antiviral therapy. Cell De Vlaminck, I., Khush, K. K., Strehl, C., Kohli, B., Luikart, H., Neff, N. F., Okamoto, J., Snyder, T. M., Cornfield, D. N., Nicolls, M. R., Weill, D., Bernstein, D., Valantine, H. A., Quake, S. R. 2013; 155 (5): 1178-1187

  Abstract

  There are few substantive methods to measure the health of the immune system, and the connection between immune strength and the viral component of the microbiome is poorly understood. Organ transplant recipients are treated with posttransplant therapies that combine immunosuppressive and antiviral drugs, offering a window into the effects of immune modulation on the virome. We used sequencing of cell-free DNA in plasma to investigate drug-virome interactions in a cohort of organ transplant recipients (656 samples, 96 patients) and find that antivirals and immunosuppressants strongly affect the structure of the virome in plasma. We observe marked virome compositional dynamics at the onset of the therapy and find that the total viral load increases with immunosuppression, whereas the bacterial component of the microbiome remains largely unaffected. The data provide insight into the relationship between the human virome, the state of the immune system, and the effects of pharmacological treatment and offer a potential application of the virome state to predict immunocompetence.

  View details for DOI 10.1016/j.cell.2013.10.034

  View details for PubMedID 24267896

• Acute respiratory distress syndrome in children: physiology and management. Current opinion in pediatrics Cornfield, D. N. 2013; 25 (3): 338-343

  Abstract

  The present review seeks to review the pathophysiologic processes that underlie the development of acute respiratory distress syndrome (ARDS) in children. The review intends to provide the physiologic foundation for the treatment strategies that are associated with the most optimal outcome.In infants and children, ARDS remains a significant cause of morbidity and mortality. Although any infant or child can develop ARDS, children who have experienced trauma, pneumonia, aspiration, or immune compromise are at increased risk. Data indicate that adoption of an open-lung ventilation strategy, characterized by sufficient positive end-expiratory pressure to avoid atelectasis, a tidal volume that is limited to less than 5-7 cc/kg per breath and a plateau pressure of 30 cm of water or less provides the greatest likelihood of survival and minimizes lung injury. The relative benefits of strategies such as high frequency oscillatory ventilation, surfactant replacement therapy and inhaled nitric oxide are considered.ARDS remains a cause of significant mortality and morbidity in children. By employing sound physiologic principles, clinical outcomes can be optimized.

  View details for DOI 10.1097/MOP.0b013e328360bbe7

  View details for PubMedID 23657244

• Embedding time-limited laboratory orders within computerized provider order entry reduces laboratory utilization*. Pediatric critical care medicine Pageler, N. M., Franzon, D., Longhurst, C. A., Wood, M., Shin, A. Y., Adams, E. S., Widen, E., Cornfield, D. N. 2013; 14 (4): 413-419

  Abstract

  : To test the hypothesis that limits on repeating laboratory studies within computerized provider order entry decrease laboratory utilization.: Cohort study with historical controls.: A 20-bed PICU in a freestanding, quaternary care, academic children's hospital.: This study included all patients admitted to the pediatric ICU between January 1, 2008, and December 31, 2009. A total of 818 discharges were evaluated prior to the intervention (January 1, 2008, through December 31, 2008) and 1,021 patient discharges were evaluated postintervention (January 1, 2009, through December 31, 2009).: A computerized provider order entry rule limited the ability to schedule repeating complete blood cell counts, chemistry, and coagulation studies to a 24-hour interval in the future. The time limit was designed to ensure daily evaluation of the utility of each test.: Initial analysis with t tests showed significant decreases in tests per patient day in the postintervention period (complete blood cell counts: 1.5 ± 0.1 to 1.0 ± 0.1; chemistry: 10.6 ± 0.9 to 6.9 ± 0.6; coagulation: 3.3 ± 0.4 to 1.7 ± 0.2; p < 0.01, all variables vs. preintervention period). Even after incorporating a trend toward decreasing laboratory utilization in the preintervention period into our regression analysis, the intervention decreased complete blood cell counts (p = 0.007), chemistry (p = 0.049), and coagulation (p = 0.001) tests per patient day.: Limits on laboratory orders within the context of computerized provider order entry decreased laboratory utilization without adverse affects on mortality or length of stay. Broader application of this strategy might decrease costs, the incidence of iatrogenic anemia, and catheter-associated bloodstream infections.

  View details for DOI 10.1097/PCC.0b013e318272010c

  View details for PubMedID 23439456

• Creation and retention of the next generation of physician-scientists for child health research. JAMA : the journal of the American Medical Association Cornfield, D. N., Lane, R., Abman, S. H. 2013; 309 (17): 1781-1782

  View details for DOI 10.1001/jama.2013.2258

  View details for PubMedID 23632720

• Hypoxia-inducible factor-1a in pulmonary artery smooth muscle cells lowers vascular tone by decreasing myosin light chain phosphorylation. Circulation research Kim, Y., Barnes, E. A., Alvira, C. M., Ying, L., Reddy, S., Cornfield, D. N. 2013; 112 (9): 1230-1233

  Abstract

  Hypoxia-inducible factor-1α (HIF-1α), an oxygen (O2)-sensitive transcription factor, mediates transcriptional responses to low-O2 tension states. Although acute hypoxia causes pulmonary vasoconstriction and chronic hypoxia can cause vascular remodeling and pulmonary hypertension, conflicting data exist on the role of HIF-1α in modulating pulmonary vascular tone.To investigate the role of smooth muscle cell (SMC)-specific HIF-1α in regulating pulmonary vascular tone.Mice with an SMC-specific deletion of HIF-1α (SM22α-HIF-1α(-/-)) were created to test the hypothesis that pulmonary artery SMC (PASMC) HIF-1α modulates pulmonary vascular tone and the response to hypoxia. SM22α-HIF-1α(-/-) mice exhibited significantly higher right ventricular systolic pressure compared with wild-type littermates under normoxia and with exposure to either acute or chronic hypoxia in the absence of histological evidence of accentuated vascular remodeling. Moreover, myosin light chain phosphorylation, a determinant of SMC tone, was higher in PASMCs isolated from SM22α-HIF-1α(-/-) mice compared with wild-type PASMCs, during both normoxia and after acute hypoxia. Further, overexpression of HIF-1α decreased myosin light chain phosphorylation in HIF-1α-null SMCs.In both normoxia and hypoxia, PASMC HIF-1α maintains low pulmonary vascular tone by decreasing myosin light chain phosphorylation. Compromised PASMC HIF-1α expression may contribute to the heightened vasoconstriction that characterizes pulmonary hypertension.

  View details for DOI 10.1161/CIRCRESAHA.112.300646

  View details for PubMedID 23513056

• Hypoxia-inducible factor-1a in pulmonary artery smooth muscle cells lowers vascular tone by decreasing Myosin light chain phosphorylation. Circulation research Kim, Y., Barnes, E. A., Alvira, C. M., Ying, L., Reddy, S., Cornfield, D. N. 2013; 112 (9): 1230-1233

  View details for DOI 10.1161/CIRCRESAHA.112.300646

  View details for PubMedID 23513056

• Voltage-Dependent Anion Channel-2 Interaction with Nitric Oxide Synthase Enhances Pulmonary Artery Endothelial Cell Nitric Oxide Production AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY Alvira, C. M., Umesh, A., Husted, C., Ying, L., Hou, Y., Lyu, S., Nowak, J., Cornfield, D. N. 2012; 47 (5): 669-678

  Abstract

  Increased pulmonary artery endothelial cell (PAEC) endothelium-dependent nitric oxide synthase (eNOS) activity mediates perinatal pulmonary vasodilation. Compromised eNOS activity is central to the pathogenesis of persistent pulmonary hypertension of the newborn (PPHN). Voltage-derived anion channel (VDAC)-1 was recently demonstrated to bind eNOS in the systemic circulation. We hypothesized that VDAC isoforms modulate eNOS activity in the pulmonary circulation, and that decreased VDAC expression contributes to PPHN. In PAECs derived from an ovine model of PPHN: (1) there is eNOS activity, but not expression; and (2) VDAC1 and -2 proteins are decreased. Immunocytochemistry, coimmunoprecipitation, and in situ proximity ligation assays in human PAECs (hPAECs) demonstrate binding between eNOS and both VDAC1 and -2, which increased upon stimulation with NO agonists. The ability of agonists to increase the eNOS/VDAC interaction was significantly blunted in hypertensive, compared with normotensive, ovine PAECs. Depletion of VDAC2, but not VDAC1, blocked the agonist-induced increase in eNOS activity in hPAECs. Overexpression of VDAC2 in hypertensive PAECs increased eNOS activity. Binding of VDAC2 enhances eNOS activity in the pulmonary circulation, and diminished VDAC2 constrains eNOS in PAECs derived from fetal lambs with chronic intrauterine pulmonary hypertension. We speculate that decreases in VDAC2 may contribute to the limited eNOS activity that characterizes pulmonary hypertension.

  View details for DOI 10.1165/rcmb.2011-0436OC

  View details for PubMedID 22842492

• Quantitative Analysis of the Human Airway Microbial Ecology Reveals a Pervasive Signature for Cystic Fibrosis SCIENCE TRANSLATIONAL MEDICINE Blainey, P. C., Milla, C. E., Cornfield, D. N., Quake, S. R. 2012; 4 (153)

  Abstract

  Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding the CF transmembrane conductance regulator. Disruption of electrolyte homeostasis at mucosal surfaces leads to severe lung, pancreatic, intestinal, hepatic, and reproductive abnormalities. Loss of lung function as a result of chronic lung disease is the primary cause of death from CF. Using high-throughput sequencing to survey microbes in the sputum of 16 CF patients and 9 control individuals, we identified diverse microbial communities in the healthy samples, contravening conventional wisdom that healthy airways are not significantly colonized. Comparing these communities with those from the CF patients revealed significant differences in microbial ecology, including differential representation of uncultivated phylotypes. Despite patient-specific differences, our analysis revealed a focal microbial profile characteristic of CF. The profile differentiated case and control groups even when classically recognized CF pathogens were excluded. As a control, lung explant tissues were also processed from a group of patients with pulmonary disease. The findings in lung tissue corroborated the presence of taxa identified in the sputum samples. Comparing the sequencing results with clinical data indicated that diminished microbial diversity is associated with severity of pulmonary inflammation within our adult CF cohort.

  View details for DOI 10.1126/scitranslmed.3004458

  View details for Web of Science ID 000309525600003

  View details for PubMedID 23019655

• Inhibiting NF-kappa B in the developing lung disrupts angiogenesis and alveolarization AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Iosef, C., Alastalo, T., Hou, Y., Chen, C., Adams, E. S., Lyu, S., Cornfield, D. N., Alvira, C. M. 2012; 302 (10): L1023-L1036

  Abstract

  Bronchopulmonary dysplasia (BPD), a chronic lung disease of infancy, is characterized by arrested alveolar development. Pulmonary angiogenesis, mediated by the vascular endothelial growth factor (VEGF) pathway, is essential for alveolarization. However, the transcriptional regulators mediating pulmonary angiogenesis remain unknown. We previously demonstrated that NF-κB, a transcription factor traditionally associated with inflammation, plays a unique protective role in the neonatal lung. Therefore, we hypothesized that constitutive NF-κB activity is essential for postnatal lung development. Blocking NF-κB activity in 6-day-old neonatal mice induced the alveolar simplification similar to that observed in BPD and significantly reduced pulmonary capillary density. Studies to determine the mechanism responsible for this effect identified greater constitutive NF-κB in neonatal lung and in primary pulmonary endothelial cells (PEC) compared with adult. Moreover, inhibiting constitutive NF-κB activity in the neonatal PEC with either pharmacological inhibitors or RNA interference blocked PEC survival, decreased proliferation, and impaired in vitro angiogenesis. Finally, by chromatin immunoprecipitation, NF-κB was found to be a direct regulator of the angiogenic mediator, VEGF-receptor-2, in the neonatal pulmonary vasculature. Taken together, our data identify an entirely novel role for NF-κB in promoting physiological angiogenesis and alveolarization in the developing lung. Our data suggest that disruption of NF-κB signaling may contribute to the pathogenesis of BPD and that enhancement of NF-κB may represent a viable therapeutic strategy to promote lung growth and regeneration in pulmonary diseases marked by impaired angiogenesis.

  View details for DOI 10.1152/ajplung.00230.2011

  View details for PubMedID 22367785

• Decisions about life-sustaining measures in children: in whose best interests? ACTA PAEDIATRICA Cornfield, D. N., Kahn, J. P. 2012; 101 (4): 333-336

  Abstract

  As the community of physicians and nurses dedicated to the care of critically ill children has gained ever more well-developed skill sets, the decision to either continue or forego life-sustaining measures has become less time-sensitive. As a result, there is greater opportunity for careful consideration and discussion. The core principle in making decisions about whether to continue or forego life-sustaining measures is the best interests of the child. However, there are many clinical situations wherein factors other than the child's best interests may influence treatment decisions. The present report seeks to examine the notion that in the arena of paediatric critical care medicine, the decision-making process regarding life-sustaining measures may place insufficient priority upon the child's best interests. We examine actual, de-identified clinical situations, encountered in the critical care arena in two categories: (i) cases that challenge the imperative to act in the child's best interests, and (ii) cases that compromise the ability of parents and caregivers to use child-centred, best-interests approaches to decision-making. Clarity surrounding the implications of a clinical decision for the patient is essential. Decisions that are not focused squarely on the child's best interests may compromise the delivery of optimally ethical end-of-life care.The cases and analysis may benefit parents and caregivers as they struggle with the difficult ethical issues that accompany decisions to continue or forego life-sustaining measures in children.

  View details for DOI 10.1111/j.1651-2227.2011.02531.x

  View details for Web of Science ID 000300973200013

  View details for PubMedID 22103464

• Hypoxia-inducible factor-1 alpha regulates KCNMB1 expression in human pulmonary artery smooth muscle cells AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Ahn, Y., Kim, Y., Adams, E., Lyu, S., Alvira, C. M., Cornfield, D. N. 2012; 302 (3): L352-L359

  Abstract

  Previously, we observed that hypoxia increases the expression of the β1-subunit (KCNMB1) of the calcium-sensitive potassium channel (BK(Ca)). Herein, we elucidate the mechanism whereby hypoxia increases KCNMB1 expression in human pulmonary artery smooth muscle cells (hPASMC). In response to hypoxia, the expression of both the transcription factor hypoxia-inducible factor 1-α (HIF-1α) and KCNMB1 are increased. Knockdown of HIF-1α using a shRNA plasmid blocked the hypoxic induction of KCNMB1 expression. Chromatin immunoprecipitation (ChIP) demonstrated HIF-1α binding to three discrete regions of the human KCNMB1 promoter known to contain hypoxia response elements (HREs). A KCNMB1 promoter reporter assay combined with site-directed mutagenesis identified two adjacent HREs located between -3,540 bp and -3,311 bp that are essential for the hypoxic induction of KCNMB1 promoter activity. Furthermore, additional ChIP assays demonstrated recruitment of the HIF-1α transcriptional coactivator, p300, to this same promoter region. Treatment of hPASMC with the histone deacetylase inhibitor, trichostatin, prolonged the increase in KCNMB1 observed with hypoxia, suggesting that alterations in chromatin remodeling function to limit the hypoxic induction of KCNMB1. Finally, KCNMB1 knockdown potentiated the hypoxia-induced increase in cytosolic calcium in hPASMC, highlighting the contribution of the β1-subunit in modulating vascular SMC tone in response to acute hypoxia. In conclusion, HIF-1α increases KCNMB1 expression in response to hypoxia in hPASMC by binding to two HREs located at -3,540 to -3,311 of the KCNMB1 promoter. We speculate that selective modulation of KCNMB1 expression may serve as a novel therapeutic approach to address diseases characterized by an increase in vascular tone.

  View details for DOI 10.1152/ajplung.00302.2011

  View details for Web of Science ID 000300245600009

  View details for PubMedID 22114151

  View details for PubMedCentralID PMC3289270

• Society for Pediatric Research 2010 Presidential Address: Academic Pediatrics and the Narrative of Discovery PEDIATRIC RESEARCH Cornfield, D. N. 2011; 70 (3): 320-324

  View details for Web of Science ID 000294192200019

  View details for PubMedID 21822098

• Computerized Physician Order Entry With Decision Support Decreases Blood Transfusions in Children PEDIATRICS Adams, E. S., Longhurst, C. A., Pageler, N., Widen, E., Franzon, D., Cornfield, D. N. 2011; 127 (5): E1112-E1119

  Abstract

  Timely provision of evidence-based recommendations through computerized physician order entry with clinical decision support may improve use of red blood cell transfusions (RBCTs).We performed a cohort study with historical controls including inpatients admitted between February 1, 2008, and January 31, 2010. A clinical decision-support alert for RBCTs was constructed by using current evidence. RBCT orders resulted in assessment of the patient's medical record with prescriber notification if parameters were not within recommended ranges. Primary end points included the average pretransfusion hemoglobin level and the rate of RBCTs per patient-day.In total, 3293 control discharges and 3492 study discharges were evaluated. The mean (SD) control pretransfusion hemoglobin level in the PICU was 9.83 (2.63) g/dL (95% confidence interval [CI]: 9.65-10.01) compared with the study value of 8.75 (2.05) g/dL (95% CI: 8.59-8.90) (P < .0001). The wards' control value was 7.56 (0.93) g/dL (95% CI: 7.47-7.65), the study value was 7.14 (1.01) g/dL (95% CI: 6.99-7.28) (P < .0001). The control PICU rate of RBCTs per patient-day was 0.20 (0.11) (95% CI: 0.13-0.27), the study rate was 0.14 (0.04) (95% CI: 0.11-0.17) (P = .12). The PICU's control rate was 0.033 (0.01) (95% CI: 0.02-0.04), and the study rate was 0.017 (0.007) (95% CI: 0.01-0.02) (P < .0001). There was no difference in mortality rates across all cohorts.Implementation of clinical decision-support alerts was associated with a decrease in RBCTs, which suggests improved adoption of evidence-based recommendations. This strategy might be widely applied to promote timely adoption of scientific evidence.

  View details for DOI 10.1542/peds.2010-3252

  View details for Web of Science ID 000290097800002

  View details for PubMedID 21502229

• The Accreditation Council for Graduate Medical Education proposed work hour regulations PEDIATRIC CRITICAL CARE MEDICINE Goodman, D. M., Winkler, M. K., Fiser, R. T., Abd-Allah, S., Mathur, M., Rivero, N., Weiss, I. K., Peterson, B., Cornfield, D. N., Mink, R., Grayck, E. N., McCabe, M. E., Schuette, J., Nares, M. A., Totapally, B., Petrillo-Albarano, T., Wolfson, R. K., Moreland, J. G., Potter, K. E., Fackler, J., Garber, N., Burns, J. P., Shanley, T. P., Lieh-Lai, M. W., Steiner, M., Tieves, K. S., Goldsmith, M., Asuncion, A., Ross, S. L., Howell, J. D., Biagas, K., Ognibene, K., Joshi, P., Rubenstein, J. S., Kocis, K. C., Cheifetz, I. M., Turner, D. A., Doughty, L., Hall, M. W., Mason, K., Penfil, S., Morrison, W., Hoehn, K. S., Watson, R. S., Garcia, R. L., Storgion, S. A., Fleming, G. M., Castillo, L., Tcharmtchi, M. H., Taylor, R. P., Ul Haque, I., Crain, N., Baden, H. P., Lee, K. J. 2011; 12 (1): 120-121

  View details for DOI 10.1097/PCC.0b013e3181fe3d4b

  View details for Web of Science ID 000285964500040

  View details for PubMedID 21209582

• Rho kinase modulates postnatal adaptation of the pulmonary circulation through separate effects on pulmonary artery endothelial and smooth muscle cells AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Alvira, C. M., Sukovich, D. J., Lyu, S., Cornfield, D. N. 2010; 299 (6): L872-L878

  Abstract

  At birth, pulmonary vasodilation occurs concomitant with the onset of air-breathing life. Whether and how Rho kinase (ROCK) modulates the perinatal pulmonary vascular tone remains incompletely understood. To more fully characterize the separate and interactive effects of ROCK signaling, we hypothesized that ROCK has discrete effects on both pulmonary artery (PA): 1) endothelial cell (PAEC) nitric oxide (NO) production and contractile state; and 2) smooth muscle cell tone independent of endothelial NO synthase (eNOS) activity. To test these hypotheses, NO production and endothelial barrier function were determined in fetal PAEC under baseline hypoxia and following exposure to normoxia with and without treatment with Y-27632, a specific pharmacological inhibitor of ROCK. In acutely instrumented, late-gestation ovine fetuses, eNOS was inhibited by nitro-l-arginine infusion into the left PA (LPA). Subsequently, fetal lambs were mechanically ventilated (MV) with 100% oxygen in the absence (control period) and presence of Y-27632. In PAEC, treatment with Y-27632 had no effect on cytosolic calcium but did increase normoxia-induced NO production. Moreover, acute normoxia increased PAEC barrier function, an effect that was potentiated by Y-27632. In fetal lambs, MV during the control period had no effect on LPA flow. In contrast, MV after Y-27632 increased LPA flow and fetal arterial P(O)₂ (Pa(O₂)) and decreased PA pressure. In conclusion, ROCK activity modulates vascular tone in the perinatal pulmonary circulation via combined effects on PAEC NO production, barrier function, and smooth muscle tone. ROCK inhibition may represent a novel treatment strategy for neonatal pulmonary vascular disease.

  View details for DOI 10.1152/ajplung.00199.2010

  View details for Web of Science ID 000284941600016

  View details for PubMedID 20709731

  View details for PubMedCentralID PMC3006275

• Developmental Regulation of Oxygen Sensing and Ion Channels in the Pulmonary Vasculature 2008 Grover Conference on Membrane Receptors, Channels and Transporters in Pulmonary Circulation Cornfield, D. N. SPRINGER-VERLAG BERLIN. 2010: 201–220

  Abstract

  The increase in oxygen tension occurring at birth causes sustained and progressive pulmonary vasodilation. The oxygen-induced perinatal pulmonary vasodilation depends on the production of nitric oxide (NO) from the pulmonary endothelium and activation of various K(+) channels in pulmonary artery smooth muscle cells. This chapter reviews a) the oxygen-sensing mechanism that stimulates endothelial NO production; b) how K(+) channels sense changes in oxygen tension; c) whether hypoxia-inducible factor-1alpha (HIF-1alpha), a well defined hypoxia-sensitive transcription factor in adult, contributes to the regulation of NO production and K(+) channel activation; and d) whether and how dysfunctional K(+) channels contribute to the development of pulmonary hypertension in the newborns.

  View details for Web of Science ID 000293426500013

  View details for PubMedID 20204732

• HOSPITALIZATION AND DEATH RATES OF HISPANIC CYSTIC FIBROSIS PEDIATRIC PATIENTS IN CALIFORNIA Buu, M. C., Milla, C., Chan, J., Wise, P. H., Cornfield, D. N. WILEY-BLACKWELL. 2010: 390–391

  View details for Web of Science ID 000282988800558

• USING COMPUTERIZED PROVIDER ORDER ENTRY (CPOE) TO PROMOTE SUSTAINED OPTIMIZATION OF DIAGNOSTIC RADIOLOGIC SERVICE UTILIZATION 39th Critical Care Congress of the Society-of-Critical-Care-Medicine Pageler, N., Longhurst, C., Shin, A., Adams, E., Widen, E., Barth, R., Cornfield, D. LIPPINCOTT WILLIAMS & WILKINS. 2009: A363–A363

  View details for Web of Science ID 000272509900709

• Increased expression of transient receptor vanilloid channels during pregnancy regulates uterine smooth muscle cell calcium entry and contraction Becard, M., Lyu, S., Alvira, C., Adams, E., Umesh, A., Cornfield, D. MOSBY-ELSEVIER. 2009: S251

  View details for DOI 10.1016/j.ajog.2009.10.710

  View details for Web of Science ID 000279559500686

• AUTOMATED DETERMINATION OF PEDIATRIC RISK OF MORTALITY (PRISM) VIA THE ELECTRONIC MEDICAL RECORD (EMR) IMPROVES EFFICIENCY AND RELIABILITY 39th Critical Care Congress of the Society-of-Critical-Care-Medicine Pageler, N., Smith, L., Longhurst, C., Luna, N., Cornfield, D. LIPPINCOTT WILLIAMS & WILKINS. 2009: A339–A339

  View details for Web of Science ID 000272509900661

• Nuclear Factor Kappa B Mediates Postnatal Alveolarization by Promoting Pulmonary Angiogenesis via Vascular Endothelial Growth Factor Receptor-2 Regulation 82nd National Conference and Exhibitions and Scientific Sessions of the American-Heart-Association Alvira, C. M., Alastalo, T. P., Chen, C., Lyu, S., Ahn, Y., Cornfield, D. N. LIPPINCOTT WILLIAMS & WILKINS. 2009: S1090–S1090

  View details for Web of Science ID 000271831503789

• Successful treatment of severe cerebral vasospasm following hemorrhage of an arteriovenous malformation JOURNAL OF NEUROSURGERY-PEDIATRICS Pendharkar, A. V., Guzman, R., Dodd, R., Cornfield, D., Edwards, M. S. 2009; 4 (3): 266-269

  Abstract

  The authors describe the case of a 13-year-old boy who presented with an intraventricular hemorrhage caused by a left trigonal arteriovenous malformation. After an initial recovery, the patient experienced complete right-sided paresis on posthemorrhage Day 6. Severe cerebral vasospasm was found on MR angiography and confirmed on conventional cerebral angiography. Intraarterial nicardipine injection and balloon angioplasty were successfully performed with improved vasospasm and subsequent neurological recovery. Cerebral vasospasm should be considered in the differential diagnosis for neurological deterioration following an arteriovenous malformation hemorrhage, and aggressive treatment can be administered to prevent ischemia and further neurological deficits.

  View details for DOI 10.3171/2009.4.PEDS09126

  View details for Web of Science ID 000269223300012

  View details for PubMedID 19772412

• Utility of blood cultures in postoperative pediatric intensive care unit patients PEDIATRIC CRITICAL CARE MEDICINE Kiragu, A. W., Zier, J., Cornfield, D. N. 2009; 10 (3): 364-368

  Abstract

  To determine the frequency of positive blood cultures in patients with fevers in the initial 48-hour postoperative period.All patients who had blood cultures drawn during the initial 48 hours postoperatively while in the pediatric intensive care unit (PICU) at the University of Minnesota Children's Hospital-Fairview during an 18-month period were included in the current study. Six hundred two postoperative patients were admitted to the PICU during the study period. Patients with a temperature >100.4 degrees F and who had blood cultures drawn were identified. Patients for whom the operative procedure was not the first in that admission, those discharged in <48 hours, and those with an indwelling central venous catheter for >24 hours before their admission were excluded.Sixty-six of these patients were febrile and had blood cultures drawn in the initial 48 hours postoperatively. One hundred eleven blood cultures were obtained. A single (0.9%) blood culture was positive. The cost per positive culture was estimated at $23,532.Even in patients admitted to the PICU, fever in the initial 48-hour postoperative period is unlikely to represent bacteremia in low-risk pediatric patients. Blood cultures in these patients are, therefore, unlikely to yield positive results. Procurement of blood cultures in this patient population is not justified. Cessation of the practice of blood culture procurement in this patient population may both focus care and provide enable meaningful cost savings.

  View details for DOI 10.1097/PCC.0b013e3181a31bb7

  View details for Web of Science ID 000266016200014

  View details for PubMedID 19325504

• Quantitative Analysis of Longitudinal Response to Aerosolized Granulocyte-Macrophage Colony-Stimulating Factor in Two Adolescents With Autoimmune Pulmonary Alveolar Proteinosis CHEST Robinson, T. E., Trapnell, B. C., Goris, M. L., Quittell, L. M., Cornfield, D. N. 2009; 135 (3): 842-848

  Abstract

  Autoimmune pulmonary alveolar proteinosis (APAP) is characterized by autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) in blood and tissues, resulting in alveolar surfactant protein accumulation. Patients with APAP present with ground-glass opacities (GGOs) and interlobular septal thickening on thin-slice chest CT scans. Aerosolized GM-CSF therapy (aeroGM-SCF) has qualitatively improved the clinical condition of patients with APAP. This report details quantitative chest CT responses to aeroGM-CSF.Two adolescent patients (aged 16 and 19 years) with APAP were treated with aeroGM-CSF. Clinical parameters, including pulmonary function tests and chest CT scans, were obtained before and after aeroGM-CSF therapy. To evaluate the effect of the therapy, serial chest CT scans were analyzed using a novel approach permitting quantitative assessment of improvement in GGOs, lung weight, and gas volume.In association with GM-CSF treatment, nutritional status and pulmonary function improved. Quantitative analysis of the CT scans demonstrated reduction in GGOs and lung weight, concomitant with an increase in airspace volume and lung inflation. The findings were consistent with a qualitative reduction in GGOs on chest CT imaging.Quantitative analysis of CT holds promise as a sensitive diagnostic tool permitting longitudinal and objective analysis of the therapeutic response to aeroGM-CSF in patients with APAP.

  View details for DOI 10.1378/chest.08-1317

  View details for Web of Science ID 000264310500034

  View details for PubMedID 19265094

• Examination of the roles of Nkx2.1 and Fgf10 in Xenopus laevis lung development Hyatt, B. A., Einerson, D., Robertson, J., Judd, D., Einerson, B., Cornfield, D. N. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2008: 607

  View details for DOI 10.1016/j.ydbio.2008.05.454

  View details for Web of Science ID 000257734600492

• Developmental regulation of hypoxia-inducible factor 1 and prolyl-hydroxylases in pulmonary vascular smooth muscle cells Annual Meeting of the Pediatric-Academic-Societies/Society-of-Pediatric-Research Resnik, E. R., Herron, J. M., Lyut, S., Cornfield, D. N. NATL ACAD SCIENCES. 2007: 18789–94

  Abstract

  The transcriptional machinery involved in the transition of an infant from intrauterine to air-breathing life is developmentally regulated, as the fetus and adult manifest differential genetic expression. The low oxygen (O(2)) environment of the mammalian fetus and the increase in O(2) tension that occurs at birth may account for the developmentally regulated alterations in gene expression. We tested the hypothesis that hypoxia-inducible factor 1 (HIF-1) expression, an O(2)-sensitive transcription factor, is developmentally regulated. We found that in fetal pulmonary artery (PA) smooth muscle cells (SMC), fetal HIF-1 protein levels were O(2)-insensitive, whereas in adult PA SMC, hypoxia increased HIF-1 protein expression. Surprisingly, hypoxia increased HIF-1 mRNA expression in fetal, but not in adult, PA SMC. HIF-1 degradation and transcriptional activity is contingent on prolyl- and asparagyl-hydroxylases. To determine whether developmental differences in O(2) sensitivity or expression of these enzymes accounts for the divergence of HIF-1 sensitivity between fetus and adult, we studied the expression of the three most well characterized prolyl-hydroxylases, PHD1, PHD2, and PHD3, and the expression of regulators of HIF-1 transcriptional activity, asparagyl-hydroxylase, factor inhibiting HIF, and the oncogenic factor, CITED2 (CREB-binding protein/p300 interacting transactivator with ED-rich tail). We found that, as in the case of HIF-1, these genes are differentially regulated in the fetus, enabling the mammalian fetus to thrive in the low O(2) tension intrauterine environment even while rendering a newborn infant uniquely well adapted to respond to the acute increase in O(2) tension that occurs at birth.

  View details for DOI 10.1073/pnas.0706019104

  View details for Web of Science ID 000251292500079

  View details for PubMedID 18000055

  View details for PubMedCentralID PMC2141855

• The unexpected effect of cyclosporin A on CD56(+)CD16(-) and CD56(+)CD16(+) natural killer cell subpopulations BLOOD Wang, H., Grzywacz, B., Sukovich, D., McCullar, V., Cao, Q., Lee, A. B., Blazar, B. R., Cornfield, D. N., Miller, J. S., Verneris, M. R. 2007; 110 (5): 1530-1539

  Abstract

  Cyclosporin A (CSA) is commonly used to prevent graft-versus-host disease. The influence of CSA on T-cell function has been extensively investigated; however, the effect of CSA on natural killer (NK) cells is less understood. NK cells were cultured with IL-2 and IL-15 with and without CSA for 1 week. Compared with controls, CSA-treated cultures showed fewer CD56(+)CD16(+)KIR(+) NK cells and a reciprocal increase in CD56(+)CD16(-)KIR(-) cells. These changes were due mainly to a reduced proliferation of the CD56(dim) NK-cell subpopulation and a relative resistance of CD56(bright) NK cells to CSA. Following coculture with K562 targets, CSA-exposed NK cells differed from controls and lacked Ca(2+) oscillations, nuclear factor of activated T cells (NFAT) dephosphorylation, and NFAT nuclear translocation. NK cells cultured in CSA retained cytotoxicity against K562, Raji, and KIR ligand-expressing lymphoblastoid cells. NK cells cultured in CSA showed increases in NKp30 and reductions in NKp44 and NKG2D. Following IL-12 and IL-18 stimulation, CSA-treated NK cells showed more IFN-gamma-producing cells. Using in vitro NK-cell differentiation, progenitor cells gave rise to more CD56(+)KIR(-) NK cells in the presence of CSA than controls. Collectively, these studies show that CSA influences NK-cell function and phenotype, which may have important implications for graft-versus-leukemia effects.

  View details for DOI 10.1182/blood-2006-10-048173

  View details for Web of Science ID 000249151800028

  View details for PubMedID 17495133

  View details for PubMedCentralID PMC1975839

• Case-series of nurse-administered nitrous oxide for urinary catheterization in children ANESTHESIA AND ANALGESIA Zier, J. L., Drake, G. J., McCormick, P. C., Clinch, K. M., Cornfield, D. N. 2007; 104 (4): 876-879

  Abstract

  Children undergoing urologic imaging studies requiring urethral catheterization experience considerable discomfort and psychological distress. Nitrous oxide sedation may mitigate these detriments but the requirement for physician administration has limited the applicability of this technique.Registered nurses underwent the nitrous oxide training requirements prescribed for state licensure of dentists and dental hygienists, with special emphasis on pediatric sedation principles. To evaluate the safety of nurse-administered nitrous oxide, we consecutively enrolled all children (ASA PS I-II) sedated for urethral catheterization for urologic imaging in an observational trial designed to identify sedation-related adverse events.Nitrous oxide was administered on 1018 occasions. There were no major adverse events (apnea, oxygen saturation <92%). Minor adverse events (diaphoresis, nausea, vomiting) occurred in 4% of patients. Eight patients (1%) were described as over-sedated. In 11 (1%) patients, nitrous oxide provided insufficient sedation for completion of urologic imaging.Nitrous oxide sedation can be provided by a nurse-administered program in pediatric radiology. Administration of nitrous oxide for pediatric procedures by adequately trained nursing staff with appropriate multidisciplinary oversight may increase children's access to this sedative/analgesic drug.

  View details for DOI 10.1213/01.ane.0000258763.17768.ce

  View details for Web of Science ID 000245371900026

  View details for PubMedID 17377099

• Chronic intrauterine pulmonary hypertension increases capacitative calcium entry in fetal pulmonary artery smooth muscle cells AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Resnik, E. R., Keck, M., Sukovich, D. J., Herron, J. M., Cornfield, D. N. 2007; 292 (4): L953-L959

  Abstract

  Oxygen causes perinatal pulmonary dilatation. Although fetal pulmonary artery smooth muscle cells (PA SMC) normally respond to an acute increase in oxygen (O2) tension with a decrease in cytosolic calcium ([Ca2+]i), an acute increase in O2 tension has no net effect on [Ca(2+)](i) in PA SMC derived from lambs with chronic intrauterine pulmonary hypertension (PHTN). The present experimental series tests the hypothesis that an acute increase in O2 tension decreases capacitative calcium entry (CCE) in normal, but not hypertensive, fetal PA SMC. PA SMC were isolated from late-gestation fetal lambs after either ligation of the ductus arteriosus (PHTN) or sham (control) operation at 127 days gestation. PA SMC were isolated from the distal PA (>or=4th generation) and maintained under hypoxic conditions ( approximately 25 Torr) in primary culture. After fura 2 loading, apparent [Ca2+]i in PA SMC was determined as the ratio of 340- to 380-nm fluorescence intensity. Under both hypoxic and normoxic conditions, cyclopiazonic acid (CPA) increased [Ca2+]i more in PHTN than in control PA SMC. CCE was determined in PA SMC under hypoxic and normoxic conditions, after superfusion with zero extracellular Ca2+ and intracellular store depletion with CPA, followed by superfusion with Ca2+-containing solution, in the presence of the voltage-operated calcium channel blockade. CCE was increased in PHTN compared with control PA SMC under conditions of both acute and sustained normoxia. Transient receptor potential channel gene expression was greater in control compared with PHTN PA SMC. PHTN may compromise perinatal pulmonary vasodilation, in part, by modulating PA SMC CCE.

  View details for DOI 10.1152/ajplung.00327.2006

  View details for Web of Science ID 000247935500016

  View details for PubMedID 17158601

• Wnt5a is required for cardiac outflow tract septation in mice PEDIATRIC RESEARCH Schleiffarth, J. R., Person, A. D., Martinsen, B. J., Sukovich, D. J., Neumann, A., Baker, C. V., Lohr, J. L., Cornfield, D. N., Ekker, S. C., Petryk, A. 2007; 61 (4): 386-391

  Abstract

  Lack of septation of the cardiac outflow tract (OFT) results in persistent truncus arteriosus (PTA), a form of congenital heart disease. The outflow myocardium expands through addition of cells originating from the pharyngeal mesoderm referred to as secondary/anterior heart field, whereas cardiac neural crest (CNC) cell-derived mesenchyme condenses to form an aortopulmonary septum. We show for the first time that a mutation in Wnt5a in mice leads to PTA. We provide evidence that Wnt5a is expressed in the pharyngeal mesoderm adjacent to CNC cells in both mouse and chicken embryos and in the myocardial cell layer of the conotruncus at the time when CNC cells begin to form the aortopulmonary septum in mice. Although expression domains of secondary heart field markers are not altered in Wnt5a mutant embryos, the expression of CNC cell marker PlexinA2 is significantly reduced. Stimulation of CNC cells with Wnt5a protein elicits Ca2+ transients, suggesting that CNC cells are capable of responding to Wnt5a. We propose a novel model in which Wnt5a produced in the OFT by cells originating from the pharyngeal mesoderm signals to adjacent CNC cells during formation of the aortopulmonary septum through a noncanonical pathway via localized intracellular increases in Ca2+.

  View details for DOI 10.1203/pdr.0b013e3180323810

  View details for Web of Science ID 000245224400002

  View details for PubMedID 17515859

• Lung specific developmental expression of the Xenopus laevis surfactant protein C and B genes GENE EXPRESSION PATTERNS Hyatt, B. A., Resnik, E. R., Johnson, N. S., Lohr, J. L., Cornfield, D. N. 2007; 7 (1-2): 8-14

  Abstract

  Efforts to characterize the mechanisms underlying early lung development have been confounded by the absence of a model that permits study of lung development prior to the onset of endodermal differentiation. Since Xenopus laevis development occurs in an extrauterine environment, we sought to determine whether the classical molecular markers of lung development and function, surfactant protein genes, are expressed in X. laevis. Surfactant protein C (SP-C) is a specific marker for lung development, expressed early in development and exclusively in the lung. Surfactant protein B (SP-B) expression is essential for life, as its absence results in neonatal death in mice and gene mutations have been associated with neonatal respiratory failure in humans. Here, we report the cloning of the first non-mammalian SP-C and SP-B genes (termed xSP-C and xSP-B) using the Xenopus model. The processed mature translated regions of both xSP-C and xSP-B have high homology with both human and mouse genes. xSP-C and xSP-B are both expressed throughout the lung of the X. laevis swimming tadpoles soon after the initiation of lung development as assessed by RT-PCR and whole mount in situ hybridization. The temporal expression patterns of xSP-C and xSP-B are consistent with the expression patterns in mammalian models of lung development. In both the tadpole and the adult X. laevis, xSP-C and xSP-B are expressed only in lung. Knowledge of the sequence and expression pattern of these two surfactant proteins in Xenopus might allow for use of this organism to study early lung development.

  View details for DOI 10.1016/j.modgep.2006.05.001

  View details for Web of Science ID 000242739100002

  View details for PubMedID 16798105

• Acute normoxia increases fetal pulmonary artery endothelial ceff cytosolic Ca2+ via Ca2+-induced Ca2+ release Annual Meeting of the Society-for-Pediatric-Research Tirosh, R., Resnik, E. R., Herron, J., Sukovich, D. J., Hong, Z., Weir, E. K., Cornfield, D. N. INT PEDIATRIC RESEARCH FOUNDATION, INC. 2006: 258–63

  Abstract

  To test the hypothesis that an acute increase in O(2) tension increases cytosolic calcium ([Ca(2+)](i)) in fetal pulmonary artery endothelial cells (PAECs) via entry of extracellular calcium and subsequent calcium-induced calcium release (CICR) and nitric oxide release, low-passage PAECs (<10 passages) were isolated from the intralobar pulmonary artery (PA) of fetal sheep and maintained under hypoxic conditions (Po(2), 25 Torr). Using the calcium-sensitive dye fura-2, we demonstrated that acute normoxia (Po(2) = 120 Torr) increased PAECs [Ca(2+)](i) by increasing the rate of entry of extracellular calcium. In the presence of either ryanodine or 2-aminoethoxy-diphenylborate (2APB), normoxia did not lead to a sustained increase in PAECs [Ca(2+)](i) Whole-cell patch clamp studies demonstrated that acute normoxia causes PAEC membrane depolarization. When loaded with the nitric oxide (NO)-sensitive dye, DAF - FM, acute normoxia increased PAEC fluorescence. In PAECs derived from fetal lambs with pulmonary hypertension, an acute increase in O(2) tension had no effect on either [Ca(2+)](i) or NO production. Hypoxia increases loading of acetylcholine-sensitive calcium stores, as hypoxia potentiated the response to acetylcholine We conclude that acute normoxia increases [Ca(2+)](i) and NO production in normotensive but not hypertensive fetal PAECs via extracellular calcium entry and calcium release from calcium-sensitive intracellular stores.

  View details for DOI 10.1203/01.pdr.0000233077.29866.f0

  View details for Web of Science ID 000239861300004

  View details for PubMedID 16857761

• Oxygen tension modulates the expression of pulmonary vascular BKCa channel alpha- and beta-subunits AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Resnik, E., Herron, J., Fu, R., Ivy, D. D., Cornfield, D. N. 2006; 290 (4): L761-L768

  Abstract

  At birth, the lung environment changes from low to relatively high O(2) tension. Pulmonary blood flow increases and pulmonary artery pressure decreases. Recent data suggest that pulmonary vascular calcium-sensitive K(+) channel (BK(Ca)) activation mediates perinatal pulmonary vasodilation. Although BK(Ca) channel expression is developmentally regulated, the molecular mechanisms responsible for BK(Ca) expression remain unknown. We tested the hypothesis that the low-O(2) tension environment of the normal fetus modulates BK(Ca) channel expression. We analyzed BK(Ca) expression under conditions of hypoxia and normoxia both in vitro and in vivo. BK(Ca) alpha-subunit mRNA expression increased twofold in ovine pulmonary artery smooth muscle cell (PASMC) primary cultures maintained in hypoxia. In vivo, BK(Ca) expression was similarly affected by hypoxia. When adult Sprague-Dawley rats were placed in hypobaric hypoxic chambers for 3 wk, hypoxic animals showed an increase of threefold in the expression of BK(Ca) alpha- and more than twofold in the expression of BK(Ca) beta(1)-subunit mRNA. Immunochemical staining was consistent with the genetic data. To assess transcriptional activation of the beta-subunit of the BK(Ca), both BK(Ca) beta(1)- and beta(2)-subunit luciferase (K(Ca) beta:luc(+)) reporter genes were constructed. Hypoxia increased PASMC K(Ca) beta(1):luc(+) reporter expression by threefold and K(Ca) beta(2):luc(+) expression by 35%. Fetal PASMC treated with the hypoxia-inducible factor-1 mimetic deferoxamine showed a 63 and 41% increase in BK(Ca) channel alpha- and beta(1)-subunit expression, respectively. Together, these results suggest that oxygen tension modulates BK(Ca) channel subunit mRNA expression, and the regulation is, at least in part, at the transcriptional level.

  View details for DOI 10.1152/ajplung.00283.2005

  View details for Web of Science ID 000236573100016

  View details for PubMedID 16284215

• Inflammatory cytokines and the development of pulmonary complications after allogeneic hematopoietic cell transplantation in patients with inherited metabolic storage disorders BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Kbarbanda, S., Panoskaltsis-Mortari, A., Haddad, I. Y., Blazar, B. R., Orchard, P. J., Cornfield, D. N., Grewal, S. S., Peters, C., Regelmann, W. E., Milla, C. E., Baker, K. S. 2006; 12 (4): 430-437

  Abstract

  Patients with inherited metabolic storage disorders are at a higher risk of developing pulmonary complications after hematopoietic cell transplantation (HCT). This single-center prospective study of 48 consecutive inherited metabolic storage disorder patients was performed to identify risk factors for the development of pulmonary complications after HCT. Before HCT, subjects underwent bronchoalveolar lavage (BAL) for cell count, culture, nitrite levels, and analysis of proinflammatory cytokines and chemokines. The overall incidence of pulmonary complications was 52% (infectious, 23%; noninfectious, 29%) over a period of 4 years. Diffuse alveolar hemorrhage was the most frequent noninfectious complication and occurred in 19% of patients, all of whom had a diagnosis of mucopolysaccharidosis (Hurler and Maroteaux-Lamy syndromes). Levels of interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor alpha, macrophage inflammatory protein 1alpha, and granulocyte colony-stimulating factor in BAL fluid samples obtained before HCT were higher in patients with mucopolysaccharidoses than in patients with leukodystrophies. In addition, levels of IL-1beta, IL-6, IL-8, and granulocyte colony-stimulating factor were increased in the BAL fluid of patients who developed noninfectious pulmonary complications compared with those who did not develop pulmonary complications. It is interesting to note that most noninfectious pulmonary complications occurred in patients with mucopolysaccharidoses, especially diffuse alveolar hemorrhage, which occurred exclusively in patients with mucopolysaccharidoses. Higher levels of bronchial proinflammatory cytokines and chemokines may be predictive of the development of subsequent posttransplantation noninfectious complications in patients with mucopolysaccharidoses, especially those with Hurler syndrome. Larger studies will be required to further elucidate etiologic mechanisms and predictive factors.

  View details for DOI 10.1016/j.bbmt.2005.12.026

  View details for Web of Science ID 000236494600006

  View details for PubMedID 16545727

• Chronic intrauterine pulmonary hypertension selectively modifies pulmonary artery smooth muscle cell gene expression AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Resnik, E., Herron, J., Keck, M., Sukovich, D., Linden, B., Cornfield, D. N. 2006; 290 (3): L426-L432

  Abstract

  Pulmonary artery smooth muscle cell (PASMC) relaxation at birth results from an increase in cytosolic cGMP, cGMP-dependent and kinase-mediated activation of the Ca2+-sensitive K+ channel (KCa), and closure of voltage-operated Ca2+ channels (VOCC). How chronic intrauterine pulmonary hypertension compromises perinatal pulmonary vasodilation remains unknown. We tested the hypothesis that chronic intrauterine pulmonary hypertension selectively modifies gene expression to mitigate perinatal pulmonary vasodilation mediated by the cGMP kinase-KCa-VOCC pathway. PASMC were isolated from late-gestation fetal lambs that had undergone either ligation of the ductus arteriosus (hypertensive) or sham operation (control) at 127 days of gestation and were maintained under either hypoxic (approximately 25 Torr) or normoxic (approximately 120 Torr) conditions in primary culture. We studied mRNA levels for cGMP kinase Ialpha (PKG-1alpha), the alpha-chain of VOCC (Cav1.2), and the alpha-subunit of the KCa channel. Compared with control PASMC, hypertensive PASMC had decreased VOCC, KCa, and PKG-1alpha expression. In response to sustained normoxia, expression of VOCC and KCa channel decreased and expression of PKG-1alpha increased. In contrast, sustained normoxia had no effect on PKG-1alpha levels and an attenuated effect on VOCC and KCa channel expression in hypertensive PASMC. Protein expression of PKG-1alpha was consistent with the mRNA data. We conclude that chronic intrauterine pulmonary hypertension decreases PKG expression and mitigates the genetic effects of sustained normoxia on pulmonary vasodilation, because gene expression remains compromised even after sustained exposure to normoxia.

  View details for DOI 10.1152/ajplung.00281.2005

  View details for Web of Science ID 000235182700002

  View details for PubMedID 16467248

• Oxygen increases ductus arteriosus smooth muscle cytosolic calcium via release of calcium from inositol triphosphate-sensitive stores Annual Meeting of the Society-for-Pediatric-Research Keck, M., Resnik, E., Linden, B., Anderson, F., Sukovich, D. J., Herron, J., Cornfield, D. N. AMER PHYSIOLOGICAL SOC. 2005: L917–L923

  Abstract

  In utero, blood shunts away from the lungs via the ductus arteriosus (DA) and the foramen ovale. After birth, the DA closes concomitant with increased oxygen tension. The present experimental series tests the hypothesis that oxygen directly increases DA smooth muscle cell (SMC) cytosolic calcium ([Ca(2+)](i)) through inactivation of a K(+) channel, membrane depolarization, and entry of extracellular calcium. To test the hypothesis, DA SMC were isolated from late-gestation fetal lambs and grown to subconfluence in primary culture in low oxygen tension (25 Torr). DA SMC were loaded with the calcium-sensitive fluorophore fura-2 under low oxygen tension conditions and studied using microfluorimetry while oxygen tension was acutely increased (120 Torr). An acute increase in oxygen tension progressively increased DA SMC [Ca(2+)](i) by 11.7 +/- 1.4% over 40 min. The effect of acute normoxia on DA SMC [Ca(2+)](i) was mimicked by pharmacological blockade of the voltage-sensitive K(+) channel. Neither removal of extracellular calcium nor voltage-operated calcium channel blockade prevented the initial increase in DA SMC [Ca(2+)](i). Manganese quenching experiments demonstrated that acute normoxia initially decreases the rate of extracellular calcium entry. Pharmacological blockade of inositol triphosphate-sensitive, but not ryanodine-sensitive, intracellular calcium stores prevented the oxygen-induced increase in [Ca(2+)](i). Endothelin increased [Ca(2+)](i) in acutely normoxic, but not hypoxic, DA SMC. Thus acute normoxia 1) increases DA SMC [Ca(2+)](i) via release of calcium from intracellular calcium stores, and subsequent entry of extracellular calcium, and 2) potentiates the effect of contractile agonists. Prolonged patency of the DA may result from disordered intracellular calcium homeostasis.

  View details for DOI 10.1152/ajplung.00403.2004

  View details for Web of Science ID 000228265300019

  View details for PubMedID 15695541

• Extubation failure in pediatric intensive care incidence and outcomes. Pediatric critical care medicine Baisch, S. D., Wheeler, W. B., Kurachek, S. C., Cornfield, D. N. 2005; 6 (3): 312-318

  Abstract

  To evaluate the hypotheses that children requiring reintubation are at an increased risk of prolonged hospitalizations, congenital heart disease, and death compared with age- and disease-severity-matched control patients.Prospective decision to evaluate all children undergoing extubation over a 5-yr time interval (1997-2001) with retrospective analysis of all failed extubation patients.A large multidisciplinary, dual-site, single-system pediatric intensive care unit caring for critically ill and injured children.All children intubated and ventilated during the study period (1997-2001).None.Failed extubation was defined as the unanticipated requirement to replace an endotracheal tube within 48 hrs of extubation. One hundred thirty children of 3,193 pediatric intensive care unit patients failed extubation (4.1%). The median age of children who failed extubation was 6.5 months, compared with a median age of 21.3 months in the control population. The median age of failed extubation in children with cardiac disease was 9.3 months. Failed extubation patients had lengthier hospital and pediatric intensive care unit stays, longer duration of mechanical ventilation, and a higher rate of tracheostomy placement than nonfailed extubation patients (p < .001). Children with congenital heart disease who failed extubation had the longest duration of hospitalization (40.0 +/- 5.4 days). Conversely, cardiac patients who did not fail extubation had the shortest length of stay (11.2 +/- 0.4 days).In the present trial, 4.1% of mechanically ventilated children failed extubation. Pediatric intensive care unit patients with failed extubation have longer hospital, pediatric intensive care unit, and ventilator courses but are not at increased risk of death relative to nonfailed extubation patients.

  View details for PubMedID 15857531

• Natural history of pulmonary complications in children after bone marrow transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Eikenberry, M., Bartakova, H., DeFor, T., Haddad, I. Y., Ramsay, N. K., Blazar, B. R., Milla, C. E., Cornfield, D. N. 2005; 11 (1): 56-64

  Abstract

  We sought, in children after bone marrow transplantation (BMT), (1) to determine the natural history and incidence of pulmonary complications, (2) to evaluate the diagnostic yield of fiberoptic bronchoscopy and bronchoalveolar lavage (BAL); and (3) to determine the effect of bronchoscopy with lavage on patient outcome. The study design was a retrospective review in a tertiary care university hospital of all children undergoing BMT over a 5-year period. Patients were separated into 2 study groups: children with and without pulmonary complications. Pulmonary complications were defined as new or persistent pulmonary infiltrates on chest radiograph or chest computed tomography scan, respiratory symptoms, hypoxemia, or hemoptysis. Three hundred sixty-three pediatric patients underwent BMT between January 1, 1995, and December 31, 1999. Ninety patients (25%) developed pulmonary complications and were evaluated with bronchoscopy and BAL. Patients with pulmonary complications had a higher mortality (65% versus 44%; P < .01). The median posttransplantation survival for children with pulmonary complications was 258 days, compared with 1572 days in patients without pulmonary complications. The incidence of pulmonary complications was increased in patients with allogeneic BMT (P < .01). The time-dependent onset of severe (grade III to IV) graft-versus-host disease increased the relative risk of pulmonary complications by 2.0 (95% confidence interval, 1.1-3.7; P = .02). Pulmonary complications increased the time-dependent relative risk of mortality by 3.5 (95% confidence interval, 2.5-4.8). The diagnostic yield of bronchoscopy with lavage was 46% in patients undergoing BAL. Diagnostic bronchoscopy did not enhance either 30- or 100-day survival. Pathogen identification did not decrease mortality (P = .45). Pulmonary complications occur in 25% of children undergoing BMT and increase the risk of death in the first year after BMT. Although pathogen identification does not confer a survival advantage, rigorous, prospective screening may allow for earlier identification of pathogens and thereby provide a benefit to this uniquely vulnerable population.

  View details for DOI 10.1016/j.bbmt.2004.09.008

  View details for Web of Science ID 000226450300007

  View details for PubMedID 15625545

• Myeloperoxidase deficiency enhances inflammation after allogeneic marrow transplantation AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Milla, C., Yang, S. X., Cornfield, D. N., Brennan, M. L., Hazen, S. L., Panoskaltsis-Mortari, A., Blazar, B. R., Haddad, I. Y. 2004; 287 (4): L706-L714

  Abstract

  Myeloperoxidase (MPO)-derived oxidants participate in the respiratory antimicrobial defense system but are also implicated in oxidant-mediated acute lung injury. We hypothesized that MPO contributes to lung injury commonly observed after bone marrow transplantation (BMT). MPO-sufficient (MPO+/+) and -deficient (MPO-/-) mice were given cyclophosphamide and lethally irradiated followed by infusion of inflammation-inducing donor spleen T cells at time of BMT. Despite suppressed generation of nitrative stress, MPO-/- recipient mice unexpectedly exhibited accelerated weight loss and increased markers of lung dysfunction compared with MPO+/+ mice. The increased lung injury during MPO deficiency was a result of donor T cell-dependent inflammatory responses because bronchoalveolar lavage fluids (BALF) from MPO-/- mice contained increased numbers of inflammatory cells and higher levels of the proinflammatory cytokine TNF-alpha and the monocyte chemoattractant protein-1 compared with wild-type mice. Enhanced inflammation in MPO-/- mice was associated with suppressed apoptosis of BALF inflammatory cells. The inflammatory process in MPO-/- recipients was also associated with enhanced necrosis of freshly isolated alveolar type II cells, critical for preventing capillary leak. We conclude that suppressed MPO-derived oxidative/nitrative stress is associated with enhanced lung inflammation and persistent alveolar epithelial injury.

  View details for DOI 10.1152/ajplung.00015.2004

  View details for Web of Science ID 000223762200011

  View details for PubMedID 15020295

• Chronic intrauterine pulmonary hypertension compromises fetal pulmonary artery smooth muscle cell O-2 sensing AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Linden, B. C., Resnik, E. R., Hendrickson, K. J., Herron, J. M., O'Connor, T. J., Cornfield, D. N. 2003; 285 (6): L1354-L1361

  Abstract

  To test the hypothesis that chronic intrauterine pulmonary hypertension (PHTN) compromises pulmonary artery (PA) smooth muscle cell (SMC) O2 sensing, fluorescence microscopy was used to study the effect of an acute increase in Po2 on the cytosolic Ca2+ concentration ([Ca2+]i) of chronically hypoxic subconfluent monolayers of PA SMC in primary culture. PA SMCs were derived from fetal lambs with PHTN due to intrauterine ligation of the ductus arteriosus. Acute normoxia decreased [Ca2+]i in control but not PHTN PA SMC. In control PA SMC, [Ca2+]i increased after Ca2+-sensitive (KCa) and voltage-sensitive (Kv) K+ channel blockade and decreased after diltiazem treatment. In PHTN PA SMC, KCa blockade had no effect, whereas Kv blockade and diltiazem increased [Ca2+]i. Inhibition of sarcoplasmic reticulum Ca2+ ATPase activity caused a greater increase in [Ca2+]i in controls compared with PHTN PA SMC. Conversely, ryanodine caused a greater increase of [Ca2+]i in PHTN compared with control PA SMC. KCa channel mRNA is decreased and Kv channel mRNA is unchanged in PHTN PA SMC compared with controls. We conclude that PHTN compromises PA SMC O2 sensing, alters intracellular Ca2+ homeostasis, and changes the predominant ion channel that determines basal [Ca2+]i from KCa to Kv.

  View details for DOI 10.1152/ajplung.00091.2003

  View details for Web of Science ID 000186401100022

  View details for PubMedID 12882761

• A rose by any other name is yet a rose - Acute respiratory failure in children AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Cornfield, D. N., Haddad, I. Y. 2003; 168 (3): 268-269

  View details for DOI 10.1164/rccm.2305008

  View details for Web of Science ID 000184466400004

  View details for PubMedID 12888605

• Safety of inhaled nitric oxide after lung transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Cornfield, D. N., Milla, C. E., Haddad, I. Y., Barbato, J. E., Park, S. J. 2003; 22 (8): 903-907

  Abstract

  The present study tests the hypothesis that therapy with inhaled nitric oxide (iNO) at the time of lung transplantation in patients undergoing bilateral angle lung transplantation: (i) is safe; and (ii) does not increase either the duration of mechanical ventilation or the incidence of acute graft dysfunction.We conducted a prospective, non-randomized trial of iNO at 20 parts per million. The treatment group was comprised of 14 patients (10 females, 4 males) undergoing lung transplantation to address severe end-stage lung disease and pulmonary hypertension (mean pulmonary artery pressure > 30 mmHg). Clinical and histologic parameters were compared with 22 historical control subjects who were matched with the study population for age, diagnosis and disease severity (17 females, 5 males) and had undergone lung transplantation in the preceding 2-year time period. No significant differences were noted between the 2 study groups at baseline.No toxic effect of iNO treatment was evident. Although the incidence of acute graft dysfunction was the same in both groups, the occurrence of acute graft rejection in the initial 4 weeks after transplant was less frequent in the iNO group than in the control group (7% vs 32%, p = 0.05). Fifty percent of the treatment group, as compared with 22% of the control group, were discharged from the hospital within 2 weeks of the procedure (p = 0.05).Early initiation of iNO in lung transplant patients with pulmonary hypertension is safe and may decrease the incidence of acute graft rejection. We speculate that iNO may exert an immunomodulatory effect.

  View details for DOI 10.1016/S1053-2498(02)00809-4

  View details for Web of Science ID 000184634300011

  View details for PubMedID 12909471

• Continuous propofol infusion in 142 critically ill children PEDIATRICS Cornfield, D. N., Tegtmeyer, K., Nelson, M. D., Milla, C. E., Sweeney, M. 2002; 110 (6): 1177-1181

  Abstract

  In recent years, continuous intravenous propofol infusion has been widely used in pediatric intensive care units. Several case reports have raised concerns about its safety. The objective of this study was to report our experience with continuous intravenous propofol in consecutive patients during an 18-month period.The study design was a retrospective review of a case series. Case was defined as a critically ill child who was treated with continuous intravenous propofol. The attending physician staff agreed to prescribe propofol via continuous intravenous infusion at a dose not to exceed 50 microg/kg/min. The protocol allowed for each patient to receive an additional intravenous bolus of propofol at a dose of 1 mg/kg no more than once per hour. The study entailed data collection from consecutive patients who were prescribed a continuous infusion of propofol in either the pediatric intensive care unit or bone marrow transplant unit.Data from 142 patients were analyzed. Each patient enrolled was adequately sedated. Administration of propofol via continuous intravenous infusion was not associated with metabolic acidosis or hemodynamic compromise. No patient in the study group was inadvertently extubated or had a central venous catheter accidentally discontinued.Propofol can be safely and effectively used to provide sedation to critically ill infants and children. We speculate that continuous infusion of propofol for extended periods of time should not exceed 67 microg/kg/min.

  View details for PubMedID 12456916

• Pulmonary vascular K+ channel expression and vasoreactivity in a model of congenital heart disease AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Cornfield, D. N., Resnik, E. R., Herron, J. M., Reinhartz, O., Fineman, J. R. 2002; 283 (6): L1210-L1219

  Abstract

  K+ channels play an important role in mediating pulmonary vasodilation caused by increased oxygen tension, nitric oxide, alkalosis, and shear stress. To test the hypothesis that lung K+ channel gene expression may be altered by chronic increases in pulmonary blood flow, we measured gene and protein expression of calcium-sensitive (K Ca ) and voltage-gated (Kv2.1) K+ channels, and a pH-sensitive K+ channel (TASK), in distal lung from fetal lambs in which an aortopulmonary shunt was placed at 139 days gestation. Under baseline conditions, animals with an aortopulmonary shunt showed elevated pulmonary artery pressure and pulmonary blood flow compared with twin controls. Hypoxia caused a greater increase in pulmonary vascular tone in shunt animals compared with controls. Alkalosis caused pulmonary vasodilation in control but not shunt animals. To determine lung K+ channel mRNA levels, we performed quantitative RT-PCR. In comparison with control animals, lung K Ca channel mRNA content was increased in shunt animals, whereas TASK mRNA levels were decreased. There was no difference in Kv2.1 mRNA levels. Channel protein expression was consistent with these findings. We conclude that, in the presence of elevated pulmonary blood flow, K Ca channel expression is increased and TASK is decreased.

  View details for DOI 10.1152/ajplung.00428.2001

  View details for Web of Science ID 000179082700008

  View details for PubMedID 12388350

• Contribution of the K-Ca channel to membrane potential and O-2 sensitivity is decreased in an ovine PPHN model AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Olschewski, A., Hong, Z. G., Linden, B. C., Porter, V. A., Weir, E. K., Cornfield, D. N. 2002; 283 (5): L1103-L1109

  Abstract

  Ca2+-sensitive K+ (K(Ca)) channels play an important role in mediating perinatal pulmonary vasodilation. We hypothesized that lung K(Ca) channel function may be decreased in persistent pulmonary hypertension of the newborn (PPHN). To test this hypothesis, pulmonary artery smooth muscle cells (PASMC) were isolated from fetal lambs with severe pulmonary hypertension induced by ligation of the ductus arteriosus in fetal lambs at 125-128 days gestation. Fetal lambs were killed after pulmonary hypertension had been maintained for at least 7 days. Age-matched, sham-operated animals were used as controls. PASMC K+ currents and membrane potentials were recorded using amphotericin B-perforated patch-clamp techniques. The increase in whole cell current normally seen in response to normoxia was decreased (333.9 +/- 63.6% in control vs. 133.1 +/- 16.0% in hypertensive fetuses). The contribution of the K(Ca) channel to the whole cell current was diminished in hypertensive, compared with control, fetal PASMC. In PASMC from hypertensive fetuses, a change from hypoxia to normoxia caused no change in membrane potential compared with a -14.6 +/- 2.8 mV decrease in membrane potential in PASMC from control animals. In PASMC from animals with pulmonary hypertension, 4-aminopyridine (4-AP) caused a larger depolarization than iberiotoxin, whereas in PASMC from control animals, iberiotoxin caused a larger depolarization than 4-AP. These data confirm the hypothesis that the contribution of the K(Ca) channel to membrane potential and O2 sensitivity is decreased in an ovine model of PPHN, and this may contribute to the abnormal perinatal pulmonary vasoreactivity associated with PPHN.

  View details for DOI 10.1152/ajplung.00100.2002

  View details for Web of Science ID 000178515100026

  View details for PubMedID 12376364

• Interactive effects of high-frequency oscillatory ventilation and inhaled nitric oxide in acute hypoxemic respiratory failure in pediatrics CRITICAL CARE MEDICINE Dobyns, E. L., Anas, N. G., Fortenberry, J. D., Deshpande, J., Cornfield, D. N., Tasker, R. C., Liu, P., Eells, P. L., Griebel, J., Kinsella, J. P., Abman, S. H. 2002; 30 (11): 2425-2429

  Abstract

  High-frequency oscillatory ventilation (HFOV) and inhaled nitric oxide (iNO) have been reported to improve oxygenation in children with acute hypoxemic respiratory failure (AHRF), but their roles in the treatment of AHRF remains unknown. The use of HFOV improves oxygenation by increasing lung recruitment. iNO can improve oxygenation in AHRF, but it may have limited efficacy in patients with poor lung inflation. Based on these findings, we hypothesized that the combined treatment of HFOV and inhalation of low-dose NO would improve oxygenation and survival in children with severe AHRF compared with children treated with conventional mechanical ventilation (CMV) or either treatment alone.Tertiary pediatric intensive care units at seven academic centers.Post hoc analysis of data from children enrolled in a multicenter, randomized, masked study of the use of iNO in the treatment of AHRF.A total of 108 pediatric patients with AHRF defined as an oxygenation index of >15 twice within 6 hrs. Mode of ventilation (HFOV or CMV) was determined by the patient's physician based on guidelines to maximize oxygenation. The patient was then randomized to treatment with or without iNO. Comparisons were made between patients who were treated with HFOV plus iNO (n = 14), HFOV alone (n = 12), CMV plus iNO (n = 35), and CMV alone (n = 38).Ventilation with CMV or HFOV with or without iNO.We found that the change in Pao /Fio ratio was greatest in the HFOV plus iNO group compared with the other treatment groups at 4 hrs (p =.02) and 12 hrs (p =.01). After 24 hrs of treatment, both HFOV plus iNO and HFOV alone resulted in greater improvement in Pao2/Fio2 ratio than either CMV alone or CMV plus iNO (p =.005). After 72 hrs, treatment with HFOV alone resulted in a greater improvement in Pao2/Fio2 ratio than either CMV alone or CMV plus iNO (p =.03). There was no difference in predefined treatment failures between treatment groups.We conclude that the combination of HFOV with iNO causes a greater improvement in oxygenation than either treatment strategy alone in children with severe AHRF. We speculate that the enhanced lung recruitment by HFOV enhances the effects of low dose iNO on gas exchange.

  View details for DOI 10.1097/01.CCM.0000034679.86211.4D

  View details for Web of Science ID 000179322900004

  View details for PubMedID 12441749

• Oxygen-induced fetal pulmonary vasodilation is mediated by intracellular calcium activation of K-Ca channels AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Porter, V. A., Rhodes, M. T., Reeve, H. L., Cornfield, D. N. 2001; 281 (6): L1379-L1385

  Abstract

  O(2) sensing in fetal pulmonary artery smooth muscle is critically important in the successful transition to air breathing at birth. However, the mechanism by which the fetal pulmonary vasculature senses and responds to an acute increase in O(2) tension is not known. Isolated fetal pulmonary artery smooth muscle cells were kept in primary culture for 5-14 days in a hypoxic environment (20-30 mmHg). These cells showed a 25.1 +/- 1.7% decrease in intracellular calcium in response to an acute increase in O(2) tension. Low concentrations of caffeine (0.5 mM) and diltiazem also decreased intracellular calcium. The decrease in intracellular calcium concentration in response to increasing O(2) was inhibited by iberiotoxin and ryanodine. Freshly isolated fetal pulmonary artery smooth muscle cells exhibited "spontaneous transient outward currents," indicative of intracellular calcium spark activation of calcium-sensitive potassium channels. The frequency of spontaneous transient outward currents increased when O(2) tension was increased to normoxic levels. Increasing fetal pulmonary O(2) tension in acutely instrumented fetal sheep increased fetal pulmonary blood flow. Ryanodine attenuated O(2)-induced pulmonary vasodilation. This study demonstrates that fetal pulmonary vascular smooth muscle cells are capable of responding to an acute increase in O(2) tension and that this O(2) response is mediated by intracellular calcium activation of calcium-sensitive potassium channels.

  View details for Web of Science ID 000172094400010

  View details for PubMedID 11704533

• A beta-peptides enhance vasoconstriction in cerebral circulation AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Niwa, K., Porter, V. A., Kazama, K., Cornfield, D., Carlson, G. A., Iadecola, C. 2001; 281 (6): H2417-H2424

  Abstract

  Amyloid-beta (A beta)-peptides are involved in the pathophysiology of Alzheimer's dementia. We studied the effects of A beta on selected constrictor responses of cerebral circulation. Mice were anesthetized (by using urethane-chloralose) and equipped with a cranial window. Arterial pressure and blood gases were monitored and controlled. Cerebral blood flow (CBF) was monitored by a laser Doppler probe. Topical superfusion with A beta 1-40 (0.1-10 microM), but not with the reverse peptide A beta 40-1, reduced resting CBF (-29 +/- 4% at 5 microM; P < 0.05) and augmented the reduction in CBF produced by the thromboxane analog U-46619 (+45 +/- 3% at 5 microM; P < 0.05). A beta 1-40 or A beta 1-42 did not affect the reduction in CBF produced by hypocapnia. The reduction in resting CBF and the enhancement of vasoconstriction were reversed by treatment with the free radical scavengers superoxide dismutase or manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin. Substitution of the methionine residue in position 35 with norleucine, a mutation that abolishes the ability of A beta to produce free radicals, abolished its vascular effects. Nanomolar concentrations of A beta 1-40 constricted isolated pressurized middle cerebral artery segments with intrinsic tone (-16 +/- 3% at 100 nM; P < 0.05). We conclude that A beta acts directly on cerebral arteries to produce vasoconstriction and to enhance selected constrictor responses. The evidence supports the idea that A beta-induced production of reactive oxygen species plays a role in this effect. The vascular actions of A beta may contribute to the deleterious effects resulting from accumulation of this peptide in Alzheimer's dementia.

  View details for Web of Science ID 000172156200019

  View details for PubMedID 11709407

• Effects of oxidant stress on inflammation and survival of iNOS knockout mice after marrow transplantation AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Yang, S. X., Porter, V. A., Cornfield, D. N., Milla, C., Panoskaltsis-Mortari, A., Blazar, B. R., Haddad, I. Y. 2001; 281 (4): L922-L930

  Abstract

  In a model of idiopathic pneumonia syndrome after bone marrow transplantation (BMT), injection of allogeneic T cells induces nitric oxide (.NO), and the addition of cyclophosphamide (Cy) generates superoxide (O.) and a tissue-damaging nitrating oxidant. We hypothesized that.NO and O. balance are major determinants of post-BMT survival and inflammation. Inducible nitric oxide synthase (iNOS) deletional mutant mice (-/-) given donor bone marrow and spleen T cells (BMS) exhibited improved survival compared with matched BMS controls. Bronchoalveolar lavage fluids obtained on day 7 post-BMT from iNOS(-/-) BMS mice contained less tumor necrosis factor-alpha and interferon-gamma, indicating that.NO stimulated the production of proinflammatory cytokines. However, despite suppressed inflammation and decreased nitrotyrosine staining, iNOS(-/-) mice given both donor T cells and Cy (BMS + Cy) died earlier than iNOS-sufficient BMS + Cy mice. Alveolar macrophages from iNOS(-/-) BMS + Cy mice did not produce.NO but persisted to generate strong oxidants as assessed by the oxidation of the intracellular fluorescent probe 2',7'-dichlorofluorescin. We concluded that.NO amplifies T cell-dependent inflammation and addition of Cy exacerbates.NO-dependent mortality. However, the lack of.NO during Cy-induced oxidant stress decreases survival of T cell-recipient mice, most likely by generation of.NO-independent toxic oxidants.

  View details for Web of Science ID 000171020400019

  View details for PubMedID 11557596

• Polycyclic aromatic hydrocarbon diol epoxides increase cytosolic Ca2+ of airway epithelial cells AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY Jyonouchi, H., Sun, S. N., Porter, V. A., Cornfield, D. N. 2001; 25 (1): 78-83

  Abstract

  Polycyclic aromatic hydrocarbons (PAHs) increase cytosolic Ca(2+) concentration ([Ca(2+)](i)) in lymphocytes and mammary epithelial cells, but little is known regarding their effects on [Ca(2+)](i) in airway epithelium. We hypothesized that benzo[a]pyrene (BP) and/or anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), a carcinogenic BP metabolite, increases [Ca(2+)](i) in untransformed human small airway epithelial (SAE) cells and that their effects on [Ca(2+)](i) are directly proportional to carcinogenicity. SAE [Ca(2+)](i) was determined by a ratiometric digital Ca(2+) imaging system. BPDE increased SAE [Ca(2+)](i) within 20 s in media with high (1 mM) and low (10 nM) Ca(2+) at a threshold concentration of 0.2 nM. Elevation of [Ca(2+)](i) persisted longer with high Ca(2+). Neither BP nor solvent altered [Ca(2+)](i). Thapsigargin and inositol 1,4,5- phosphate receptor (InsP(3)R) antagonists inhibited this BPDE action with low Ca(2+). We conclude that BPDE but not BP increases [Ca(2+)](i) partly by mobilizing Ca(2+) from cytosolic stores through an InsP(3)R. The most potent carcinogenic PAH diol epoxide increased in SAE [Ca(2+)](i) at the lowest threshold concentration, suggesting that carcinogenicity is directly proportional to the action of PAHs on SAE [Ca(2+)](i). Short-term exposure to BPDE 36 to 48 h before the study rendered SAE cells less sensitive to BPDE, suggesting that BPDE may also induce persistent changes in Ca(2+) signaling pathways.

  View details for Web of Science ID 000170221800013

  View details for PubMedID 11472978

• Ca2+-activated K+ channels modulate basal and E-2 beta-induced rises in uterine blood flow in ovine pregnancy AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Rosenfeld, C. R., Cornfield, D. N., ROY, T. 2001; 281 (1): H422-H431

  Abstract

  Uterine blood flow (UBF) increases >30-fold during ovine pregnancy. During the last trimester, this reflects vasodilation, which may be due to placentally derived estrogens. In nonpregnant ewes, estradiol-17 beta (E(2)beta) increases UBF >10-fold by activating nitric oxide synthase and large conductance calcium-dependent potassium channels (BK(Ca)). To determine whether BK(Ca) channels modulate basal and E(2)beta-induced increases in UBF, studies were performed in near-term pregnant ewes with uterine artery flow probes and catheters for intra-arterial infusions of tetraethylammonium (TEA), a selective BK(Ca) channel antagonist at <1 mM, in the absence or presence of E(2)beta (1 microg/kg iv). Uterine arteries were collected to measure BK(Ca) channel mRNA. TEA (0.15 mM) decreased basal UBF (P < 0.0001) 40 +/- 8% and 55 +/- 7% (n = 11) at 60 and 90 min, respectively, and increased resistance 175 +/- 48% without affecting (P > 0.1) mean arterial pressure (MAP), heart rate, or contralateral UBF. Systemic E(2)beta increased UBF 30 +/- 6% and heart rate 13 +/- 1% (P < or = 0.0001, n = 13) without altering MAP. Local TEA (0.15 mM) inhibited E(2)beta-induced increases in UBF without affecting increases in heart rate (10 +/- 4%; P = 0.006). BK(Ca) channel mRNA was present in uterine artery myocytes from pregnant and nonpregnant ewes. Exponential increases in ovine UBF in late pregnancy may reflect BK(Ca) channel activation, which may be mediated by placentally derived estrogens.

  View details for Web of Science ID 000169458800051

  View details for PubMedID 11406511

• Pulmonary vascular response to normoxia and K-Ca channel activity is developmentally regulated AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Rhodes, M. T., Porter, V. A., Saqueton, C. B., Herron, J. M., Resnik, E. R., Cornfield, D. N. 2001; 280 (6): L1250-L1257

  Abstract

  To address developmental regulation of pulmonary vascular O(2) sensing, we tested the hypotheses that 1) fetal but not adult pulmonary artery smooth muscle cells (PASMCs) can directly sense an acute increase in O(2), 2) Ca2+-sensitive K(+) (K(Ca)) channel activity decreases with maturation, and 3) PASMC K(Ca) channel expression decreases with maturation. We used fluorescence microscopy to confirm that fetal but not adult PASMCs are able to sense an acute increase in O(2) tension. Acute normoxia induced a 22 +/- 2% decrease in cytosolic Ca2+ concentration ([Ca2+](i)) in fetal PASMCs and no change in ([Ca2+](i)) in adult PASMCs (P < 0.01). The effects of K(+) channel antagonists were studied on fetal and adult PASMC ([Ca2+](i)). Iberiotoxin (10(-9) M) caused PASMC ([Ca2+](i)) to increase by 694 +/- 22% in the fetus and caused no change in adult PASMCs. K(Ca) channel expression and mRNA levels in distal pulmonary arteries from fetal and adult sheep were examined. Both K(Ca) channel protein and mRNA expression in the distal pulmonary vasculature decreased with maturation. We conclude that maturation-dependent changes in PASMC O(2) sensing render the fetal PASMCs uniquely sensitive to an acute increase in O(2) tension at a biologically critical time point.

  View details for Web of Science ID 000168621700021

  View details for PubMedID 11350805

• Chronic intrauterine pulmonary hypertension decreases calcium-sensitive potassium channel mRNA expression AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Cornfield, D. N., Resnik, E. R., Herron, J. M., Abman, S. H. 2000; 279 (5): L857-L862

  Abstract

  Calcium-sensitive potassium (K(Ca)) channels play a critical role in mediating perinatal pulmonary vasodilation. Because infants with persistent pulmonary hypertension of the newborn (PPHN) have blunted vasodilator responses to birth-related stimuli, we hypothesized that lung K(Ca) channel gene expression is decreased in PPHN. To test this hypothesis, we measured K(Ca) channel gene expression in distal lung homogenates from both fetal lambs with severe pulmonary hypertension caused by prolonged compression of the ductus arteriosus and age-matched, sham-operated animals (controls). After at least 9 days of compression of the ductus arteriosus, fetal lambs were killed. To determine lung K(Ca) channel mRNA levels, primers were designed against the known sequence of the K(Ca) channel and used in semiquantitative RT-PCR, with lung 18S rRNA content as an internal control. Compared to that in control lambs, lung K(Ca) channel mRNA content in the PPHN group was reduced by 26 +/- 6% (P < 0.02), whereas lung voltage-gated K(+) 2.1 mRNA content was unchanged. We conclude that lung K(Ca) channel mRNA expression is decreased in an ovine model of PPHN. Decreased K(Ca) channel gene expression may contribute to the abnormal pulmonary vascular reactivity associated with PPHN.

  View details for Web of Science ID 000090056200010

  View details for PubMedID 11053020

• Fetal rabbit pulmonary artery smooth muscle cell response to ryanodine is developmentally regulated AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Porter, V. A., Reeve, H. L., Cornfield, D. N. 2000; 279 (4): L751-L757

  Abstract

  To study developmental changes in intracellular calcium handling in pulmonary artery smooth muscle cells (PASMCs), cells were isolated from distal and proximal pulmonary arteries from rabbits at different developmental stages: juvenile (4-6 wk old), newborn (<48 h), and full-term fetal. Isolated PASMCs were studied using the calcium-sensitive dye fura 2. Cells from each age group responded to caffeine with an increase in calcium; however, ryanodine (50 microM) only increased calcium in fetal distal PASMCs. The ryanodine-induced increase was due to influx of extracellular calcium because it was blocked by removal of extracellular calcium or by diltiazem. The calcium-sensitive potassium (K(Ca)) channel blocker iberiotoxin produced a transient increase in calcium in the fetal distal PASMCs, which could be inhibited by prior application of ryanodine. Conversely, the ryanodine response was inhibited if iberiotoxin was given first. With the use of electrophysiology and confocal microscopy, fetal PASMCs were shown to exhibit spontaneous transient outward currents and calcium sparks, respectively. These observations suggest that ryanodine-sensitive release of calcium from the sarcoplasmic reticulum and K(Ca) channels act together to control intracellular calcium only in fetal distal PASMCs.

  View details for Web of Science ID 000089467300018

  View details for PubMedID 11000136

• Voltage-gated K+-channel activity in ovine pulmonary vasculature is developmentally regulated AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Cornfield, D. N., Saqueton, C. B., Porter, V. A., Herron, J., Resnik, E., Haddad, I. Y., Reeve, H. L. 2000; 278 (6): L1297-L1304

  Abstract

  To examine mechanisms underlying developmental changes in pulmonary vascular tone, we tested the hypotheses that 1) maturation-related changes in the ability of the pulmonary vasculature to respond to hypoxia are intrinsic to the pulmonary artery (PA) smooth muscle cells (SMCs); 2) voltage-gated K(+) (K(v))-channel activity increases with maturation; and 3) O(2)-sensitive Kv2.1 channel expression and message increase with maturation. To confirm that maturational differences are intrinsic to PASMCs, we used fluorescence microscopy to study the effect of acute hypoxia on cytosolic Ca(2+) concentration ([Ca(2+)](i)) in SMCs isolated from adult and fetal PAs. Although PASMCs from both fetal and adult circulations were able to sense an acute decrease in O(2) tension, acute hypoxia induced a more rapid and greater change in [Ca(2+)](i) in magnitude in PASMCs from adult compared with fetal PAs. To determine developmental changes in K(v)-channel activity, the effects of the K(+)-channel antagonist 4-aminopyridine (4-AP) were studied on fetal and adult PASMC [Ca(2+)](i). 4-AP (1 mM) caused PASMC [Ca(2+)](i) to increase by 94 +/- 22% in the fetus and 303 +/- 46% in the adult. K(v)-channel expression and mRNA levels in distal pulmonary arteries from fetal, neonatal, and adult sheep were determined through the use of immunoblotting and semiquantitative RT-PCR. Both Kv2.1-channel protein and mRNA expression in distal pulmonary vasculature increased with maturation. We conclude that there are maturation-dependent changes in PASMC O(2) sensing that may render the adult PASMCs more responsive to acute hypoxia.

  View details for Web of Science ID 000087573600023

  View details for PubMedID 10835337

• Randomized, controlled trial of low-dose inhaled nitric oxide in the treatment of term and near-term infants with respiratory failure and pulmonary hypertension 66th Annual Meeting of the Society-for-Pediatric-Research Cornfield, D. N., Maynard, R. C., deRegnier, R. A., Guiang, S. F., Barbato, J. E., Milla, C. E. AMER ACAD PEDIATRICS. 1999: 1089–94

  Abstract

  Recent reports indicate that inhaled nitric oxide (iNO) causes selective pulmonary vasodilation, increases arterial oxygen tension, and may decrease the use of extracorporeal membrane oxygenation (ECMO) in infants with persistent pulmonary hypertension of the newborn (PPHN). Despite these reports, the optimal dose and timing of iNO administration in PPHN remains unclear.To test the hypotheses that in PPHN 1) iNO at 2 parts per million (ppm) is effective at acutely increasing oxygenation as measured by oxygenation index (OI); 2) early use of 2 ppm of iNO is more effective than control (0 ppm) in preventing clinical deterioration and need for iNO at 20 ppm; and 3) for those infants who fail the initial treatment protocol (0 or 2 ppm) iNO at 20 ppm is effective at acutely decreasing OI.A randomized, controlled trial of iNO in 3 nurseries in a single metropolitan area. Thirty-eight children, average gestational age of 37.3 weeks and average age <1 day were enrolled. Thirty-five of 38 infants had echocardiographic evidence of pulmonary hypertension. On enrollment, median OI in the control group, iNO at 0 ppm, (n = 23) was 33.1, compared with 36.9 in the 2-ppm iNO group (n = 15).Initial treatment with iNO at 2 ppm for an average of 1 hour was not associated with a significant decrease in OI. Twenty of 23 (87%) control patients and 14 of 15 (92%) of the low-dose iNO group demonstrated clinical deterioration and were treated with iNO at 20 ppm. In the control group, treatment with iNO at 20 ppm decreased the median OI from 42.6 to 23.8, whereas in the 2-ppm iNO group with a change in iNO from 2 to 20 ppm, the median OI did not change (42.6 to 42.0). Five of 15 patients in the low-dose nitric oxide group required ECMO and 2 died, compared with 7 of 23 requiring ECMO and 5 deaths in the control group.In infants with PPHN, iNO 1): at 2 ppm does not acutely improve oxygenation or prevent clinical deterioration, but does attenuate the rate of clinical deterioration; and 2) at 20 ppm acutely improves oxygenation in infants initially treated with 0 ppm, but not in infants previously treated with iNO at 2 ppm. Initial treatment with a subtherapeutic dose of iNO may diminish the clinical response to 20 ppm of iNO and have adverse clinical sequelae.

  View details for Web of Science ID 000083448000007

  View details for PubMedID 10545552

• Aerosol delivery of diethylenetriamine/nitric oxide, a nitric oxide adduct, causes selective pulmonary vasodilation in perinatal lambs JOURNAL OF LABORATORY AND CLINICAL MEDICINE Cornfield, D. N., Martin, E. B., Hampl, V., Archer, S. L. 1999; 134 (4): 419-425

  Abstract

  Postnatal adaptation of the pulmonary circulation is mediated partly by endothelium-derived nitric oxide (NO). Recent studies have demonstrated that inhaled NO causes selective and sustained vasodilation in infants with persistent pulmonary hypertension of the newborn. Because the short half-life of NO limits its clinical application, we hypothesized that aerosol delivery of an NO-adduct, diethylenetriamine (DETANO), can cause sustained and selective pulmonary vasodilation. To test the acute effects of DETANO, we studied the pulmonary vascular response of late-gestation fetal lambs (n = 8; age = 138 days; term = 147) to aerosolized DETANO in the presence of an endothelium-derived NO inhibitor, nitro-L-arginine. To determine whether DETANO has a sustained effect, fetal lambs were ventilated with FiO2 0.10 before and 15 minutes after they were treated with aerosolized DETANO. Fetal lambs were acutely prepared. Nitro-L-arginine (1 mg/min x 30 minutes) was infused into the left pulmonary artery before ventilation with FiO2 1.00 for 30 minutes, followed by continued ventilation with FiO2 0.10 for 10 minutes. This represented the control period. Ventilation was continued with FiO2 1.00, and aerosolized DETANO was given in doses of 0.1, 0.4, and 1.0 mg. Fifteen minutes after the last dose of DETANO was administered, animals were ventilated with FiO2 0.10. In the control period, during ventilation with FiO2 0.10, left pulmonary artery flow was 122+/-33 mL/min and decreased to 104+/-22 mL/min. Aerosol delivery of DETANO increased left pulmonary artery flow to 176+/-26 mL/min (P<.05) and had no effect on aortic pressure or heart rate. After DETANO was administered, ventilation with FiO2 0.10 did not cause any change in left pulmonary artery flow. We conclude that DETANO can cause selective fetal pulmonary vasodilation. Aerosol delivery of DETANO may increase the clinical applications of NO.

  View details for Web of Science ID 000083205500014

  View details for PubMedID 10521090

• Inhaled nitric oxide in premature neonates with severe hypoxaemic respiratory failure: a randomised controlled trial LANCET Kinsella, J. P., Walsh, W. F., Bose, C. L., Gerstmann, D. R., LaBella, J. J., Sardesai, S., Walsh-Sukys, M. C., McCaffrey, M. J., Cornfield, D. N., Bhutani, V. K., Cutter, G. R., Baier, M., Abman, S. H. 1999; 354 (9184): 1061-1065

  Abstract

  Inhaled nitric oxide improves oxygenation and lessens the need for extracorporeal-membrane oxygenation in full-term neonates with hypoxaemic respiratory failure and persistent pulmonary hypertension, but potential adverse effects are intracranial haemorrhage and chronic lung disease. We investigated whether low-dose inhaled nitric oxide would improve survival in premature neonates with unresponsive severe hypoxaemic respiratory failure, and would not increase the frequency or severity of intracranial haemorrhage or chronic lung disease.We did a double-blind, randomised controlled trial in 12 perinatal centres that provide tertiary care. 80 premature neonates (gestational age < or = 34 weeks) with severe hypoxaemic respiratory failure were randomly assigned inhaled nitric oxide (n=48) or no nitric oxide (n=32, controls). Our primary outcome was survival to discharge. Analysis was by intention to treat. We studied also the rate and severity of intracranial haemorrhage, pulmonary haemorrhage, duration of ventilation, and chronic lung disease at 36 weeks' postconceptional age.The two groups did not differ for baseline characteristics or severity of disease. Inhaled nitric oxide improved oxygenation after 60 min (p=0.03). Survival at discharge was 52% in the inhaled-nitric-oxide group and 47% in controls (p=0.65). Causes of death were mainly related to extreme prematurity and were similar in the two groups. The two groups did not differ for adverse events or outcomes (intracranial haemorrhage grade 2-4, 28% inhaled nitric oxide and 33% control; pulmonary haemorrhage 13% and 9%; chronic lung disease 60% and 80%).Low-dose inhaled nitric oxide improved oxygenation but did not improve survival in severely hypoxaemic premature neonates. Low-dose nitric oxide in the most critically ill premature neonates does not increase the risk of intracranial haemorrhage, and may decrease risk of chronic lung injury.

  View details for Web of Science ID 000082777500010

  View details for PubMedID 10509496

• Interactions of keratinocyte growth factor with a nitrating species after marrow transplantation in mice AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Haddad, I. Y., Panoskaltsis-Mortari, A., Ingbar, D. H., Resnik, E. R., Yang, S. X., Farrell, C. L., Lacey, D. L., Cornfield, D. N., Blazar, B. R. 1999; 277 (2): L391-L400

  Abstract

  We reported that allogeneic T cells given to irradiated mice at the time of marrow transplantation stimulated tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and nitric oxide (. NO) production in the lung, and the addition of cyclophosphamide (known to stimulate superoxide production) favored the generation of a nitrating species. Although keratinocyte growth factor (KGF) prevents experimental lung injury by promoting epithelial repair, its effects on the production of inflammatory mediators has not been studied. KGF given before transplantation inhibited the T cell-induced increase in bronchoalveolar lavage fluid protein, TNF-alpha, IFN-gamma, and nitrite levels measured on day 7 after transplantation without modifying cellular infiltration or proinflammatory cytokines and inducible. NO synthase mRNA. KGF also suppressed. NO production by alveolar macrophages obtained from mice injected with T cells. In contrast, the same schedule of KGF failed to prevent permeability edema or suppress TNF-alpha, IFN-gamma, and. NO production in mice injected with both T cells and cyclophosphamide. Because only epithelial cells respond to KGF, these data are consistent with the production of an epithelial cell-derived mediator capable of downregulating macrophage function. However, the presence of a nitrating agent impairs KGF-derived responses.

  View details for Web of Science ID 000081904000020

  View details for PubMedID 10444534

• NO causes perinatal pulmonary vasodilation through K+-channel activation and intracellular Ca2+ release AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Saqueton, C. B., Miller, R. B., Porter, V. A., Milla, C. E., Cornfield, D. N. 1999; 276 (6): L925-L932

  Abstract

  Evidence suggests that nitric oxide (NO) causes perinatal pulmonary vasodilation through K+-channel activation. We hypothesized that this effect worked through cGMP-dependent kinase-mediated activation of Ca2+-activated K+ channel that requires release of intracellular Ca2+ from a ryanodine-sensitive store. We studied the effects of 1) K+-channel blockade with tetraethylammonium, 4-aminopyridine, a voltage-dependent K+-channel blocker, or glibenclamide, an ATP-sensitive K+-channel blocker; 2) cyclic nucleotide-sensitive kinase blockade with either KT-5823, a guanylate-sensitive kinase blocker, or H-89, an adenylate-sensitive kinase blocker; and 3) blockade of intracellular Ca2+ release with ryanodine on NO-induced pulmonary vasodilation in acutely prepared late-gestation fetal lambs. N-nitro-L-arginine, a competitive inhibitor of endothelium-derived NO synthase, was infused into the left pulmonary artery, and tracheotomy was placed. The animals were ventilated with 100% oxygen for 20 min, followed by ventilation with 100% oxygen and inhaled NO at 20 parts/million (ppm) for 20 min. This represents the control period. In separate protocols, the animals received an intrapulmonary infusion of the different blockers and were ventilated as above. Tetraethylammonium (n = 6 animals) and KT-5823 (n = 4 animals) attenuated the response, whereas ryanodine (n = 5 animals) blocked NO-induced perinatal pulmonary vasodilation. 4-Aminopyridine (n = 5 animals), glibenclamide (n = 5 animals), and H-89 (n = 4 animals) did not affect NO-induced pulmonary vasodilation. We conclude that NO causes perinatal pulmonary vasodilation through cGMP-dependent kinase-mediated activation of Ca2+-activated K+ channels and release of Ca2+ from ryanodine-sensitive stores.

  View details for Web of Science ID 000080822700005

  View details for PubMedID 10362716

• Multicenter randomized controlled trial of the effects of inhaled nitric oxide therapy on gas exchange in children with acute hypoxemic respiratory failure JOURNAL OF PEDIATRICS Dobyns, E. L., Cornfeld, D. N., Anas, N. G., Fortenberry, J. D., Tasker, R. C., Lynch, A., Liu, P., Eells, P. L., Griebel, J., Baier, M., Kinsella, J. P., Abman, S. H. 1999; 134 (4): 406-412

  Abstract

  To determine whether inhaled nitric oxide (iNO) therapy can attenuate the progression of lung disease in acute hypoxemic respiratory failure, we performed a multicenter, randomized, masked, controlled study of the effects of prolonged iNO therapy on oxygenation. We hypothesized that iNO therapy would improve oxygenation in an acute manner, slow the rate of decline in gas exchange, and decrease the number of patients who meet pre-established oxygenation failure criteria.A total of 108 children (median age 2.5 years) with severe acute hypoxemic respiratory failure from 7 centers were enrolled. After consent was obtained, patients were randomized to treatment with iNO (10 ppm) or mechanical ventilation alone for at least 72 hours. Patients with an oxygenation index >/=40 for 3 hours or >/=25 for 6 hours were considered treatment failures and exited the study.Patient age, primary diagnosis, pediatric risk of mortality score, mode of ventilation, and median oxygenation index (35 +/- 22 vs 30 +/- 15; iNO vs control; mean +/- SEM) were not different between groups at study entry. Comparisons of oxygenation indexes during the first 12 hours demonstrated an acute improvement in oxygenation in the iNO group at 4 hours (-10.2 vs -2.7, mean values; P <.014) and at 12 hours (-9.2 vs -2.8; P <.007). At 12 hours 36% of the control group met failure criteria in contrast with 16% in the iNO group (P <.05). During prolonged therapy the failure rate was reduced in the iNO group in patients whose entry oxygenation index was >/=25 (P <.04) and in immunocompromised patients (P <.03).We conclude that iNO causes an acute improvement in oxygenation in children with severe AHRF. Two subgroups (immunocompromised and an entry oxygen index >/=25) appear to have a more sustained improvement in oxygenation, and we speculate that these subgroups may benefit from prolonged therapy.

  View details for Web of Science ID 000079648400005

  View details for PubMedID 10190913

• K+-channel blockade inhibits shear stress-induced pulmonary vasodilation in the ovine fetus AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Storme, L., Rairigh, R. L., Parker, T. A., Cornfield, D. N., Kinsella, J. P., Abman, S. H. 1999; 276 (2): L220-L228

  Abstract

  To determine whether K+-channel activation mediates shear stress-induced pulmonary vasodilation in the fetus, we studied the hemodynamic effects of K+-channel blockers on basal pulmonary vascular resistance and on the pulmonary vascular response to partial compression of the ductus arteriosus (DA) in chronically prepared late-gestation fetal lambs (128-132 days gestation). Study drugs included tetraethylammonium (TEA; Ca2+-dependent K+-channel blocker), glibenclamide (Glib; ATP-dependent K+-channel blocker), charybdotoxin (CTX; preferential high-conductance Ca2+-dependent K+-channel blocker), apamin (Apa; low-conductance Ca2+-dependent K+-channel blocker), and 4-aminopyridine (4-AP; voltage-dependent K+-channel blocker). Catheters were inserted in the left pulmonary artery (LPA) for selective drug infusion and in the main pulmonary artery, aorta, and left atrium to measure pressure. An inflatable vascular occluder was placed around the DA. LPA flow was measured with an ultrasonic flow transducer. Animals were treated with saline, high- or low-dose TEA, Glib, Apa, CTX, CTX plus Apa, or 4-AP injected into the LPA. DA compression caused a time-related decrease in pulmonary vascular resistance in the control, Glib, Apa, CTX, CTX plus Apa, and low-dose TEA groups but not in the high-dose TEA and 4-AP groups. These data suggest that pharmacological blockade of Ca2+- and voltage-dependent K+-channel activity but not of low-conductance Ca2+- and ATP-dependent K+-channel activity attenuates shear stress-induced fetal pulmonary vasodilation.

  View details for Web of Science ID 000078492900002

  View details for PubMedID 9950883

• Effects of inhaled nitric oxide and oxygen in high-altitude pulmonary edema 70th Scientific Session of the American-Heart-Association Anand, I. S., Prasad, B. A., Chugh, S. S., Rao, K. R., Cornfield, D. N., Milla, C. E., Singh, N., Singh, S., Selvamurthy, W. LIPPINCOTT WILLIAMS & WILKINS. 1998: 2441–45

  Abstract

  High-altitude pulmonary edema (HAPE) is characterized by pulmonary hypertension, increased pulmonary capillary permeability, and hypoxemia. Treatment is limited to descent to lower altitude and administration of oxygen.We studied the acute effects of inhaled nitric oxide (NO), 50% oxygen, and a mixture of NO plus 50% oxygen on hemodynamics and gas exchange in 14 patients with HAPE. Each gas mixture was given in random order for 30 minutes followed by 30 minutes washout with room air. All patients had severe HAPE as judged by Lake Louise score (6.4+/-0.7), PaO2 (35+/-3. 1 mm Hg), and alveolar to arterial oxygen tension difference (AaDO2) (26+/-3 mm Hg). NO had a selective effect on the pulmonary vasculature and did not alter systemic hemodynamics. Compared with room air, pulmonary vascular resistance fell 36% with NO (P<0.001), 23% with oxygen (P<0.001 versus air, P<0.05 versus NO alone), and 54% with NO plus 50% oxygen (P<0.001 versus air, P<0.005 versus oxygen and versus NO). NO alone improved PaO2 (+14%) and AaDO2 (-31%). Compared with 50% oxygen alone, NO plus 50% oxygen had a greater effect on AaDO2 (-18%) and PaO2 (+21%).Inhaled NO may have a therapeutic role in the management of HAPE. The combined use of inhaled NO and oxygen has additive effects on pulmonary hemodynamics and even greater effects on gas exchange. These findings indicate that oxygen and NO may act on separate but interactive mechanisms in the pulmonary vasculature.

  View details for Web of Science ID 000077278100015

  View details for PubMedID 9832490

• A maturational shift in pulmonary K+ channels, from Ca2+ sensitive to voltage dependent AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Reeve, H. L., Weir, E. K., Archer, S. L., Cornfield, D. N. 1998; 275 (6): L1019-L1025

  Abstract

  The mechanism responsible for the abrupt decrease in resistance of the pulmonary circulation at birth may include changes in the activity of O2-sensitive K+ channels. We characterized the electrophysiological properties of fetal and adult ovine pulmonary arterial (PA) smooth muscle cells (SMCs) using conventional and amphotericin B-perforated patch-clamp techniques. Whole cell K+ currents of fetal PASMCs in hypoxia were small and characteristic of spontaneously transient outward currents. The average resting membrane potential (RMP) was -36 +/- 3 mV and could be depolarized by charybdotoxin (100 nM) or tetraethylammonium chloride (5 mM; both blockers of Ca2+-dependent K+ channels) but not by 4-aminopyridine (4-AP; 1 mM; blocker of voltage-gated K+ channels) or glibenclamide (10 microM; blocker of ATP-dependent K+ channels). In hypoxia, chelation of intracellular Ca2+ by 5 mM 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid further reduced the amplitude of the whole cell K+ current and prevented spontaneously transient outward current activity. Under these conditions, the remaining current was partially inhibited by 1 mM 4-AP. K+ currents of fetal PASMCs maintained in normoxia were not significantly reduced by acute hypoxia. In normoxic adult PASMCs, whole cell K+ currents were large and RMP was -49 +/- 3 mV. These 4-AP-sensitive K+ currents were partially inhibited by exposure to acute hypoxia. We conclude that the K+ channel regulating RMP in the ovine pulmonary circulation changes after birth from a Ca2+-dependent K+ channel to a voltage-dependent K+ channel. The maturational-dependent differences in the mechanism of the response to acute hypoxia may be due to this difference in K+ channels.

  View details for Web of Science ID 000077747100001

  View details for PubMedID 9843837

• Mechanisms of pulmonary vasodilatation and ductus arteriosus constriction by normoxia Conference on Oxygen Homeostasis and Its Dynamics Weir, E. K., Reeve, H. L., Tolarova, S., Cornfield, D. N., Nelson, D. P., Archer, S. L. SPRINGER-VERLAG TOKYO. 1998: 400–409

  View details for Web of Science ID 000082188300050

• Diversity of response in vascular smooth muscle cells to changes in oxygen tension Meeting on Forefronts in Nephrology: Oxygen Sensing on the Cellular and Molecular Levels Weir, E. K., Reeve, H. L., Cornfield, D. N., TRISTANIFIROUZI, M., Peterson, D. A., Archer, S. L. NATURE PUBLISHING GROUP. 1997: 462–66

  Abstract

  Hypoxia causes pulmonary vasoconstriction (HPV), but also dilation of systemic vessels and the ductus arteriosus. In the adult animal. HPV is initiated by inhibition of potassium current (IK) in the smooth muscle cells of small resistance arteries, which results in membrane depolarization and calcium entry through voltage-gated calcium channels. The oxygen-sensitive channels that initiate HPV are 4-aminopyridine (4-AP)-sensitive delayed rectifier channels (KDR), the most prominent of which has a conductance of 37 pS. In the fetus, hypoxia causes pulmonary vasoconstriction through inhibition of a calcium-sensitive potassium channel (KCa). In smooth muscle cells from the rabbit ductus arteriosus, which dilates in response to hypoxia, whole-cell potassium current is reversibly enhanced, rather than inhibited, by hypoxia. The principal oxygen-sensitive channel is inhibited by 4-AP and has a conductance of about 58 pS. There are morphological and electrophysiological differences between individual pulmonary artery smooth muscle cells, for example, in some cells IK is predominantly carried by KDR channels and in others by KCa channels. KDR cells are more common in the resistance pulmonary arteries and KCa in the conduit arteries. Responses of specific vessels (conduit, resistance; pulmonary, systemic, ductus) at different stages of development (fetal, neonatal and adult) to changes in oxygen tension may be determined by the distribution of a variety of ion channels in the smooth muscle cells.

  View details for Web of Science ID A1997WF30700015

  View details for PubMedID 9027722

• Ventilation-induced pulmonary vasodilation at birth is modulated by potassium channel activity AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY TRISTANIFIROUZI, M., Martin, E. B., Tolarova, S., Weir, E. K., Archer, S. L., Cornfield, D. N. 1996; 271 (6): H2353-H2359

  Abstract

  At birth, pulmonary blood flow rapidly increases 8- to 10-fold, and pulmonary arterial pressure falls by 50% within 24 h. The postnatal adaptation of the pulmonary circulation is mediated, in part, by endothelium-derived nitric oxide (EDNO). Recent studies suggest that EDNO may reduce vascular resistance, in part, by activating K+ channels. We hypothesized that K+ channels modulate the changes in pulmonary hemodynamics associated with birth. To test this hypothesis, we studied the effect of K+ channel inhibition on two separate, but interdependent stimuli: 1) mechanical ventilation with low inspired O2 concentrations (designed to maintain normal fetal blood gas tensions) and 2) mechanical ventilation with high inspired O2 concentrations. Tetraethyl-ammonium (TEA, 1 mg/min for 100 min; n = 5), a nonspecific K+ channel blocker, glibenclamide (Gli, 1 mg/min for 30 min; n = 6), an ATP-sensitive K+ channel blocker, or saline (n = 7) was infused into the left pulmonary artery (LPA) of acutely instrumented fetal lambs. The umbilical-placental circulation remained intact, and lambs were ventilated with 0.10 inspired O2 concentration (FIO2) for 60 min, followed by 1.0 FIO2 for 20 min. Neither TEA nor Gli had an effect on basal pulmonary tone. TEA attenuated the increase in LPA flow and decrease in pulmonary vascular resistance in response to mechanical ventilation with 0.10 and 1.0 FIO2; Gli had no effect. These results support the hypothesis that non-ATP-sensitive K+ channels modulate the transition from fetal to neonatal pulmonary circulation.

  View details for Web of Science ID A1996WB84000019

  View details for PubMedID 8997293

• Oxygen causes fetal pulmonary vasodilation through activation of a calcium-dependent potassium channel PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Cornfield, D. N., Reeve, H. L., Tolarova, S., Weir, E. K., Archer, S. 1996; 93 (15): 8089-8094

  Abstract

  At birth, pulmonary vasodilation occurs as air-breathing life begins. The mechanism of O2-induced pulmonary vasodilation is unknown. We proposed that O2 causes fetal pulmonary vasodilation through activation of a calcium-dependent potassium channel (KCa) via a cyclic nucleotide-dependent kinase. We tested this hypothesis in hemodynamic studies in acutely prepared fetal lambs and in patch-clamp studies on resistance fetal pulmonary artery smooth muscle cells. Fetal O2 tension (PaO2) was increased by ventilating the ewe with 100% O2, causing fetal total pulmonary resistance to decrease from 1.18 +/- 0.14 to 0.41 +/- 0.03 mmHg per ml per min. Tetraethylammonium and iberiotoxin, preferential KCa-channel inhibitors, attenuated O2-induced fetal pulmonary vasodilation, while glibenclamide, an ATP-sensitive K+-channel antagonist, had no effect. Treatment with either a guanylate cyclase antagonist (LY83583) or cyclic nucleotide-dependent kinase inhibitors (H-89 and KT 5823) significantly attenuated O2-induced fetal pulmonary vasodilation. Under hypoxic conditions (PaO2 = 25 mmHg), whole-cell K+-channel currents (Ik) were small and were inhibited by 1 mM tetraethylammonium or 100 nM charybdotoxin (CTX; a specific KCa-channel blocker). Normoxia (PaO2 = 120 mmHg) increased Ik by more than 300%, and this was reversed by 100 nM CTX. Nitric oxide also increased Ik. Resting membrane potential was -37.2 +/- 1.9 mV and cells depolarized on exposure to CTX, while hyperpolarizing in normoxia. We conclude that O2 causes fetal pulmonary vasodilation by stimulating a cyclic nucleotide-dependent kinase, resulting in KCa-channel activation, membrane hyperpolarization, and vasodilation.

  View details for Web of Science ID A1996UY93000122

  View details for PubMedID 8755608

• Inhalational nitric oxide in pulmonary parenchymal and vascular disease JOURNAL OF LABORATORY AND CLINICAL MEDICINE Cornfield, D. N., Abman, S. H. 1996; 127 (6): 530-539

  View details for Web of Science ID A1996UR63100004

  View details for PubMedID 8648257

• HYPOXIA POTENTIATES NITRIC-OXIDE SYNTHESIS AND TRANSIENTLY INCREASES CYTOSOLIC CALCIUM LEVELS IN PULMONARY-ARTERY ENDOTHELIAL-CELLS EUROPEAN RESPIRATORY JOURNAL Hampl, V., Cornfield, D. N., Cowan, N. J., Archer, S. L. 1995; 8 (4): 515-522

  Abstract

  There is indirect, contradictory evidence both for increased and reduced synthesis of the endothelium-derived vasodilator, nitric oxide, in the pulmonary circulation during acute hypoxia. Therefore, we decided to directly measure the effect of acute hypoxia on nitric oxide production by cultured pulmonary endothelium. Because increases in the intracellular free calcium concentration are known to initiate nitric oxide synthesis, we also studied cytosolic calcium levels. We measured the accumulation of the stable nitric oxide metabolite, nitrite, in the fluid used to superfuse the cultured bovine pulmonary artery endothelial cells at an oxygen tension (PO2) of either 20.3 (normoxia) or 4.9 kPa (hypoxia) (152 or 37 mmHg). Intracellular calcium levels were measured with dual-excitation microfluorimetry after loading the cells with the fluorescent calcium indicator, fura 2. Basal NO synthesis, measured as nitrite accumulation over 10 min, was significantly higher under hypoxic than normoxic conditions (8.3 +/- 2.2 versus 4.6 +/- 0.8 nM). Hypoxia transiently increased cytosolic calcium concentration (from 113 +/- 10 to 231 +/- 45 nM). Ryanodine and thapsigargin (which deplete intracellular calcium stores), but not the removal of extracellular calcium, inhibited the hypoxic increase in cytosolic calcium, indicating that it resulted primarily from release of intracellular calcium. Bradykinin-elicited NO synthesis was potentiated by hypoxia. Bradykinin-induced increase in cytosolic calcium was not inhibited by hypoxia. We conclude that hypoxia acutely increases cytosolic calcium levels and basal and bradykinin-stimulated nitric oxide synthesis in pulmonary artery endothelium.

  View details for Web of Science ID A1995QZ17400002

  View details for PubMedID 7664847

• CA2+-INHIBITABLE ADENYLYL-CYCLASE MODULATES PULMONARY-ARTERY ENDOTHELIAL-CELL CAMP CONTENT AND BARRIER FUNCTION PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Stevens, T., Nakahashi, Y., Cornfield, D. N., McMurtry, I. F., Cooper, D. M., Rodman, D. M. 1995; 92 (7): 2696-2700

  Abstract

  Maintenance by the endothelium of a semi-permeable barrier is critically important in the exchange of oxygen and carbon dioxide in the lung. Intracellular free Ca2+ ([Ca2+]i) and cAMP are principal determinants of endothelial cell barrier function through their mutually opposing actions on endothelial retraction. However, details of the mechanisms of this antagonism are lacking. The recent discovery that certain adenylyl cyclases (EC 4.6.1.1) could be acutely inhibited by Ca2+ in the intracellular concentration range provided one possible mechanism whereby elevated [Ca2+]i could decrease cAMP content. This possibility was explored in pulmonary artery endothelial cells. The results indicate that a type VI Ca(2+)-inhibitable adenylyl cyclase exists in pulmonary artery endothelial cells and is modulated by physiological changes in [Ca2+]i. Furthermore, the results suggest the inverse relationship between [Ca2+]i and cAMP that is established by Ca(2+)-inhibitable adenylyl cyclase plays a critical role in modulating pulmonary artery endothelial cell permeability. These data provide evidence that susceptibility to inhibition of adenylyl cyclase by Ca2+ can be exploited in modulating a central physiological process.

  View details for Web of Science ID A1995QP88900059

  View details for PubMedID 7708708

• REDUCED PO2 ALTERS THE BEHAVIOR OF FURA-2 AND INDO-1 IN BOVINE PULMONARY-ARTERY ENDOTHELIAL-CELLS CELL CALCIUM Stevens, T., Fouty, B., Cornfield, D., Rodman, D. M. 1994; 16 (5): 404-412

  Abstract

  Calcium-sensitive fluorophores are used to estimate cytosolic free Ca2+ in many cell types under various conditions. We tested the effect of reduced PO2 on the behavior of Fura-2 and Indo-1 in cultured bovine pulmonary artery endothelial cells. Reduced PO2 (PO2 25-35 mmHg) caused a significant upward shift of in vivo calibration curves for both fluorophores. The in vivo emission spectrum of Fura-2 indicated that the effect was principally due to attenuated emission at the Ca(2+)-unbound 380 nm wavelength, with no shift in position of the emission maxima for either Ca(2+)-bound or unbound forms of the fluorophore. Reduced PO2 did not directly alter the behavior of the dyes, as no shift of in vitro calibration curves was seen. Neither decreased photobleaching nor altered autofluorescence accounted for the shift. We investigated several potential indirect effects, including cellular acidification, reduced viscosity, inhibition of oxidative energy production and reductive stress. In contrast to lowered PO2, acidification in vitro produced a leftward but not an upward shift. Estimation of intracellular pH with SNAFL-calcein under reduced PO2 showed no apparent acidification in these cells, further strengthening the argument that altered intracellular pH was not causing the shift. Others have shown that decreases in viscosity in vitro may shift the calibration curve for Fura-2 upward, similar to our finding with reduced PO2. However, for Indo-1 we found that decreased viscosity in vitro attenuated fluorescence emission at the Ca(2+)-bound 405 nm wavelength, thus producing the opposite effect on fluorescence ratio and indicating that reduced PO2 was not acting through changes in cellular microviscosity.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1994PR18300007

  View details for PubMedID 7859254

• ACUTE REDUCTIONS IN PO-2 DEPOLARIZE PULMONARY-ARTERY ENDOTHELIAL-CELLS AND DECREASE [CA2+](I) AMERICAN JOURNAL OF PHYSIOLOGY Stevens, T., Cornfield, D. N., McMurtry, I. F., Rodman, D. M. 1994; 266 (4): H1416-H1421

  Abstract

  Whereas pulmonary artery endothelial cells (PAECs) are sensitive to oxygen, neither the effect of an acute reduction in PO2 on PAEC membrane potential nor its effect on intracellular free Ca2+ ([Ca2+]i) is known. We hypothesized that in confluent primary cultures of PAECs, an acute decrease in PO2 would depolarize the cell membrane, inhibit Ca2+ influx, and reduce [Ca2+]i. To test this hypothesis, the membrane-sensitive fluorophore bis (1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC4, 1 microM) and [Ca2+]i-sensitive probe fura 2 (3 microM) were used. A decrease in PO2 from 125 to 35 mmHg caused membrane depolarization and a 60 +/- 8% (data are means +/- SE) reduction in Ca2+ influx, estimated by manganese quenching of fura 2 fluorescence. While basal [Ca2+]i was 79 +/- 5 nM in normoxic cells, it decreased to 31 +/- 2 nM after 15 min of hypoxia. Decreasing the electrochemical gradient for Ca2+ entry with either low extracellular Ca2+, the K+ channel blockers tetraethylammonium or charybdotoxin, or blockade of Ca2+ entry with lanthanum decreased [Ca2+]i by 54-71% of that observed during an acute reduction in PO2. These results demonstrate that an acute reduction in PO2 1) depolarizes PAECs, 2) reduces Ca2+ influx, and 3) decreases [Ca2+]i, and that a similar reduction in [Ca2+]i was observed with interventions designed to reduce the electrochemical driving force for Ca2+ entry.

  View details for Web of Science ID A1994NJ99600019

  View details for PubMedID 8184919

• ACUTE-HYPOXIA CAUSES MEMBRANE DEPOLARIZATION AND CALCIUM INFLUX IN FETAL PULMONARY-ARTERY SMOOTH-MUSCLE CELLS AMERICAN JOURNAL OF PHYSIOLOGY Cornfield, D. N., Stevens, T., McMurtry, I. F., Abman, S. H., Rodman, D. M. 1994; 266 (4): L469-L475

  Abstract

  Changes in oxygen tension in the perinatal period contribute to high pulmonary vascular tone in the fetus and the decline in resistance that occurs at birth. Distal pulmonary artery smooth muscle cells (PASMC) isolated from late-gestation ovine fetuses respond to acute hypoxia with an increase in cytosolic calcium concentration ([Ca2+]i) dependent on Ca2+ entry. The purpose of this study is to determine 1) whether acute hypoxia results in PASMC membrane depolarization, 2) whether Ca2+ entry was through voltage-operated calcium channels (VOCC), 3) the contribution of Ca(2+)-induced Ca2+ release (CICR) to the hypoxic response, and 4) whether a subset of K+ channels might serve as oxygen sensors in fetal PASMC. We used microfluorimetry on subconfluent monolayers of PASMC in primary culture loaded with either a membrane potential-sensitive dye, bis(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC4; DPASMC), to estimate membrane potential, or the Ca(2+)-sensitive fluorophore, fura 2, to measure [Ca2+]i. Hypoxia increased fluorescence from PASMC loaded with DiBAC4, consistent with membrane depolarization. Verapamil (an inhibitor of VOCC) attenuated, and BAY K 8644 (a VOCC facilitator) potentiated, the hypoxia-induced increase in [Ca2+]i, respectively. The hypoxic response was transient after treatment with ryanodine (10(-7) M), a blocker of calcium release from intracellular stores. Charybdotoxin (10(-7) M), an inhibitor of Ca(2+)-activated K+ channels, almost doubled [Ca2+]i, whereas glibenclamide (10(-5) M), an ATP-sensitive K(+)-channel antagonist, had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1994NJ99400089

  View details for PubMedID 7513965

• ACUTE-HYPOXIA INCREASES CYTOSOLIC CALCIUM IN FETAL PULMONARY-ARTERY SMOOTH-MUSCLE CELLS AMERICAN JOURNAL OF PHYSIOLOGY Cornfield, D. N., Stevens, T., McMurtry, I. F., Abman, S. H., Rodman, D. M. 1993; 265 (1): L53-L56

  Abstract

  We studied the effect of acute hypoxia on the cytosolic calcium concentration ([Ca2+]i) of fetal vascular smooth muscle cells (SMC) from late gestation fetal lambs. We tested the following hypotheses: 1) fetal pulmonary artery (PA) SMC sense hypoxia; 2) hypoxia stimulates transmembrane Ca2+ influx causing increased basal [Ca2+]i and Ca2+ responses to pharmacological vasoconstrictors; and 3) the response is unique to SMC from small (near resistance) PA. Fetal SMC were isolated from the proximal and distal pulmonary (DPA) and carotid arteries of late-gestation ovine fetuses, maintained in culture for 5-14 days prior to study, and studied with dual-excitation microfluorimetry using fura 2. Acute hypoxia caused a 233% increase in [Ca2+]i in distal PA SMC (P < 0.01), which was absent in low extracellular calcium bath. [Ca2+]i increased transiently in normoxic DPA SMC treated with angiotensin II, and oscillations in [Ca2+]i occurred (amplitude > or = 30 nM). In hypoxic DPA SMC the increase in [Ca2+]i was sustained and oscillations were attenuated or absent. [Ca2+]i in proximal PA SMC did not change with exposure to acute hypoxia and carotid artery SMC [Ca2+]i decreased by 13% (P < 0.05). We conclude that fetal SMC isolated from the DPA of late-gestation ovine fetuses directly sense decreased oxygen tension with an increase in [Ca2+]i that is dependent on the entry of extracellular Ca2+.

  View details for Web of Science ID A1993LP43100098

  View details for PubMedID 8338182

• EFFECTS OF OXYGEN AND EXOGENOUS L-ARGININE ON EDRF ACTIVITY IN FETAL PULMONARY CIRCULATION AMERICAN JOURNAL OF PHYSIOLOGY MCQUESTION, J. A., Cornfield, D. N., McMurtry, I. F., Abman, S. H. 1993; 264 (3): H865-H871

  Abstract

  To determine whether L-arginine, the precursor of endothelium-derived relaxing factor (EDRF), increases vasodilator activity in the fetal pulmonary circulation, we studied its effects on basal pulmonary vascular tone and on pulmonary vasodilation stimulated by oxygen and acetylcholine (ACh) in chronically prepared late-gestation fetal lambs. L-Arginine infusion (30-300 mg over 10 min) into the left pulmonary artery (LPA) increased blood flow (18-57%) without changing pulmonary artery pressure. To determine whether O2-induced vasodilation involves EDRF and is augmented by L-arginine treatment, we infused L-arginine or NG-nitro-L-arginine (L-NNA), an inhibitor of EDRF synthesis, while increasing fetal PO2 6 Torr by delivering 100% O2 to the ewe for 120 min. In controls, LPA blood flow progressively increased from 106 +/- 13 ml/min (baseline) to 257 +/- 34 ml/min (peak) at 40 min of increased PO2 (P < 0.05, baseline vs. peak) but steadily returned toward baseline during the next hour. Treatment with L-NNA markedly attenuated O2-induced pulmonary vasodilation (P < 0.05 vs. control). L-Arginine infusion did not augment or sustain the O2-induced vasodilator response. We also examined whether L-arginine could sustain pulmonary vasodilation to ACh, another EDRF-dependent stimulus, and found that the EDRF substrate neither potentiated nor sustained the ACh response. We conclude that: in the fetal lung 1) exogenous L-arginine is a fetal pulmonary vasodilator, 2) increased PO2 augments EDRF activity in the fetal lung, and 3) supplemental L-arginine does not sustain either O2- or ACh-induced vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1993KV27100028

  View details for PubMedID 8456989

• ROLE OF ENDOTHELIUM-DERIVED NITRIC-OXIDE IN PERINATAL PULMONARY VASOREGULATION NATO Advanced Research Workshop: The 6th Glover Conference on the Pulmonary Circulation Abman, S. H., Cornfield, D. N., Kinsella, J. P. PLENUM PRESS DIV PLENUM PUBLISHING CORP. 1993: 331–344

  View details for Web of Science ID A1993BZ59L00024

• ROLE OF ATP-SENSITIVE POTASSIUM CHANNELS IN OVINE FETAL PULMONARY VASCULAR TONE AMERICAN JOURNAL OF PHYSIOLOGY Cornfield, D. N., MCQUESTON, J. A., McMurtry, I. F., Rodman, D. M., Abman, S. H. 1992; 263 (5): H1363-H1368

  Abstract

  To study the potential role of ATP-sensitive K+ (K+ATP) channels in fetal pulmonary vasoregulation, we studied the effect of a K+ATP channel agonist, lemakalim, and antagonist, glibenclamide, on the fetal pulmonary circulation in nine chronically instrumented late-gestation fetal lambs. Left pulmonary artery (LPA) blood flow was measured with an electromagnetic flow transducer. Brief (10 min) infusions of lemakalim at 3, 10, and 30 micrograms/min into the LPA produced dose-dependent increases in flow from 68 +/- 7 to 96 +/- 11, 160 +/- 15, and 204 +/- 34 ml/min, respectively. The duration of pulmonary vasodilation after the 10-min infusions of lemakalim at 3, 10, and 30 micrograms/min was 20 +/- 3, 47 +/- 10, and 55 +/- 15 min, respectively. Pulmonary blood pressure and flow did not change with intrapulmonary infusion of glibenclamide (10 mg), a K+ATP channel antagonist. Lemakalim-induced pulmonary vasodilation was not affected by nitro-L-arginine (10 mg), a competitive inhibitor of endothelium-dependent relaxing factor, but was blocked by glibenclamide. Prolonged (2 h) intrapulmonary infusions of lemakalim (2-6 micrograms/min) increased pulmonary blood flow by 137%. The increase in pulmonary blood flow was sustained throughout the infusion. Systemic and pulmonary arterial pressures decreased during prolonged infusion. We conclude that K+ATP channels are present in the fetal pulmonary circulation, but do not participate in the regulation of basal pulmonary vascular tone. K+ATP channel activation produces sustained vasodilation that is not mediated by endothelium-derived relaxing factor. We speculate that birth-related stimuli activate K+ATP channels to enhance the pulmonary vasodilation that occurs at birth.

  View details for Web of Science ID A1992JZ77900005

  View details for PubMedID 1443190

• EFFECTS OF BIRTH-RELATED STIMULI ON L-ARGININE-DEPENDENT PULMONARY VASODILATION IN OVINE FETUS AMERICAN JOURNAL OF PHYSIOLOGY Cornfield, D. N., CHATFIELD, B. A., MCQUESTON, J. A., McMurtry, I. F., Abman, S. H. 1992; 262 (5): H1474-H1481

  Abstract

  To determine the effects of birth-related stimuli on L-arginine-dependent vasodilation or nitric oxide (NO) activity in the perinatal lung, we studied the fetal pulmonary vascular effects of nitro-L-arginine (L-NA), a specific inhibitor of NO formation, during 1) mechanical ventilation without altering fetal blood gas tensions; 2) administration of high oxygen concentrations; and 3) increased flow or shear stress. In the first protocol, 13 late-gestation fetal lambs were ventilated with low fraction of inspired oxygen concentration (FIO2 less than or equal to 0.10) for 60 min after infusion of L-NA or saline into the left pulmonary artery (LPA). In control animals, LPA flow steadily increased during 60 min of ventilation. With L-NA treatment, the rise in flow and decrease in total pulmonary resistance (TPR) were reduced 67% (P less than 0.001 vs. control) and 28% (P less than 0.01 vs. control), respectively. Subsequent ventilation with high FIO2 (1.00) decreased mean pulmonary arterial pressure (PAP) in control but not in L-NA-treated animals. TPR remained fourfold greater in L-NA-treated animals than in control animals (P less than 0.001). In the second protocol, with partial compression of the ductus arteriosus, LPA flow increased 300% and TPR decreased 61% over 30 min. After L-NA treatment the rise in blood flow and decrease in TPR was markedly attenuated (P less than 0.001). We conclude that the perinatal pulmonary vasodilator response to ventilation without changing arterial oxygen tension and ventilation with increased oxygen tension are modulated by NO.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1992HV37200023

  View details for PubMedID 1590451