Shravani Pasupneti

All Publications

• The Role of Regulatory T Cells in Pulmonary Arterial Hypertension. Frontiers in immunology Tian, W., Jiang, S. Y., Jiang, X., Tamosiuniene, R., Kim, D., Guan, T., Arsalane, S., Pasupneti, S., Voelkel, N. F., Tang, Q., Nicolls, M. R. 2021; 12: 684657

  Abstract

  Pulmonary arterial hypertension (PAH) is a chronic, incurable condition characterized by pulmonary vascular remodeling, perivascular inflammation, and right heart failure. Regulatory T cells (Tregs) stave off autoimmunity, and there is increasing evidence for their compromised activity in the inflammatory milieu of PAH. Abnormal Treg function is strongly correlated with a predisposition to PAH in animals and patients. Athymic Treg-depleted rats treated with SU5416, an agent causing pulmonary vascular injury, develop PAH, which is prevented by infusing missing CD4+CD25highFOXP3+ Tregs. Abnormal Treg activity may also explain why PAH disproportionately affects women more than men. This mini review focuses on the role of Tregs in PAH with a special view to sexual dimorphism and the future promise of Treg therapy.

  View details for DOI 10.3389/fimmu.2021.684657

  View details for PubMedID 34489935

• Endothelial HIF-2alpha as a Key Endogenous Mediator Preventing Emphysema. American journal of respiratory and critical care medicine Pasupneti, S., Tian, W., Tu, A. B., Dahms, P., Granucci, E., Gandjeva, A., Xiang, M., Butcher, E., Semenza, G. L., Tuder, R., Jiang, X., Nicolls, M. R. 2020

  Abstract

  RATIONALE: Endothelial injury may provoke emphysema, but molecular pathways of disease development require further discernment. Emphysema lungs exhibit decreased expression of hypoxia inducible factor-2alpha (HIF-2alpha)-regulated genes, and tobacco smoke decreases pulmonary HIF-2alpha levels. These findings suggest that decreased HIF-2alpha expression is important in the development of emphysema.OBJECTIVES: The objective of this study was to evaluate the roles of endothelial cell (EC) HIF-2alpha in the pathogenesis of emphysema in mice.METHODS: Mouse lungs were examined for emphysema following either the loss or overexpression of EC Hif-2alpha. Additionally, SU5416, a VEGFR2 inhibitor, was used to induce emphysema. Lungs were evaluated for hepatocyte growth factor (HGF), a protein involved in alveolar development and homeostasis. Patient emphysema lungs were measured for endothelial HIF-2alpha expression.MEASUREMENTS AND MAIN RESULTS: EC Hif-2alpha deletion resulted in emphysema, in association with fewer ECs and pericytes. Following SU5416 exposure, EC Hif-2alpha knockout mice developed more severe emphysema, whereas EC Hif-2alpha-overexpressing mice were protected. EC Hif-2alpha knockout mice demonstrated lower levels of HGF. Human emphysema lung samples exhibited reduced EC HIF-2alpha expression.CONCLUSIONS: Here, we demonstrate a unique, protective role for pulmonary endothelial HIF-2alpha and how decreased expression of this endogenous factor causes emphysema; its pivotal protective function is suggested by its ability to overcome VEGF antagonism. HIF-2alpha may maintain alveolar architecture by promoting vascular survival and associated HGF production. In summary, HIF-2alpha may be a key endogenous factor that prevents the development of emphysema, and its upregulation has the potential to foster lung health in at-risk patients.

  View details for DOI 10.1164/rccm.202001-0078OC

  View details for PubMedID 32515984

• Decreased lymphatic HIF-2α accentuates lymphatic remodeling in lymphedema. The Journal of clinical investigation Jiang, X. n., Tian, W. n., Granucci, E. J., Tu, A. B., Kim, D. n., Dahms, P. n., Pasupneti, S. n., Peng, G. n., Kim, Y. n., Lim, A. H., Espinoza, F. H., Cribb, M. n., Dixon, J. B., Rockson, S. G., Semenza, G. L., Nicolls, M. R. 2020

  Abstract

  Pathologic lymphatic remodeling in lymphedema evolves during periods of tissue inflammation and hypoxia through poorly defined processes. In human and mouse lymphedema, there is a significant increase of hypoxia inducible factor (HIF)-1α, but a reduction of HIF-2α protein expression in lymphatic endothelial cells (LECs). We questioned whether dysregulated expression of these transcription factors contributes to disease pathogenesis and found that LEC-specific deletion of Hif-2α exacerbated lymphedema pathology. Even without lymphatic vascular injury, the loss of LEC-specific Hif-2α caused anatomic pathology and a functional decline in fetal and adult mice. These findings suggest that HIF-2α is an important mediator of lymphatic health. HIF-2α promoted protective phosphorylated TIE2 (p-TIE2) signaling in LECs, a process also replicated by upregulating TIE2 signaling through adenovirus-mediated angiopoietin-1 (Angpt1) gene therapy. Our study suggests that HIF-2α normally promotes healthy lymphatic homeostasis and raises the exciting possibility that restoring HIF-2α pathways in lymphedema could mitigate long-term pathology and disability.

  View details for DOI 10.1172/JCI136164

  View details for PubMedID 32673288

• Airway hypoxia in lung transplantation CURRENT OPINION IN PHYSIOLOGY Pasupneti, S., Nicolls, M. R. 2019; 7: 21–26

  View details for DOI 10.1016/j.cophys.2018.12.002

  View details for Web of Science ID 000471295100005

• Phenotypically-Silent Bone Morphogenetic Protein Receptor 2 (Bmpr2) Mutations Predispose Rats to Inflammation-Induced Pulmonary Arterial Hypertension by Enhancing The Risk for Neointimal Transformation. Circulation Tian, W. n., Jiang, X. n., Sung, Y. K., Shuffle, E. n., Wu, T. H., Kao, P. N., Tu, A. B., Dorfmüller, P. n., Cao, A. n., Wang, L. n., Peng, G. n., Kim, Y. n., Zhang, P. n., Chappell, J. n., Pasupneti, S. n., Dahms, P. n., Maguire, P. n., Chaib, H. n., Zamanian, R. n., Peters-Golden, M. n., Snyder, M. P., Voelkel, N. F., Humbert, M. n., Rabinovitch, M. n., Nicolls, M. R. 2019

  Abstract

  Bmpr2 mutations are critical risk factors for hereditary pulmonary arterial hypertension (hPAH) with approximately 20% of carriers developing disease. There is an unmet medical need to understand how environmental factors, such as inflammation, render Bmpr2 mutants susceptible to PAH. Overexpressing 5-lipoxygenase (5-LO) provokes lung inflammation and transient PAH in Bmpr2+/- mice. Accordingly, 5-LO and its metabolite, leukotriene B4 (LTB4), are candidates for the 'second hit'. The purpose of this study was to determine how 5-LO-mediated pulmonary inflammation synergized with phenotypically-silent Bmpr2 defects to elicit significant pulmonary vascular disease in rats.Monoallelic Bmpr2 mutant rats were generated and found phenotypically normal for up to one year of observation. To evaluate whether a second hit would elicit disease, animals were exposed to 5-LO-expressing adenovirus (AdAlox5), monocrotaline, SU5416, SU5416 with chronic hypoxia or chronic hypoxia alone. Bmpr2-mutant hPAH patient samples were assessed for neointimal 5-LO expression. Pulmonary artery endothelial cells (PAECs) with impaired BMPR2 signaling were exposed to increased 5-LO-mediated inflammation and were assessed for phenotypic and transcriptomic changes.Lung inflammation, induced by intratracheal delivery of AdAlox5, elicited severe PAH with intimal remodeling in Bmpr2+/- rats but not in their wild-type littermates. Neointimal lesions in the diseased Bmpr2+/- rats gained endogenous 5-LO expression associated with elevated LTB4 biosynthesis. Bmpr2-mutant hPAH patients similarly expressed 5-LO in the neointimal cells. In vitro, BMPR2 deficiency, compounded by 5-LO-mediated inflammation, generated apoptosis-resistant, and proliferative PAECs with mesenchymal characteristics. These transformed cells expressed nuclear envelope-localized 5-LO consistent with induced LTB4 production, as well as a transcriptomic signature similar to clinical disease, including upregulated NF-κB, IL-6, and TGF-β signaling pathways. The reversal of PAH and vasculopathy in Bmpr2 mutants by TGF-β antagonism suggests that TGF-β is critical for neointimal transformation.In a new 'two-hit' model of disease, lung inflammation induced severe PAH pathology in Bmpr2+/- rats. Endothelial transformation required the activation of canonical and noncanonical TGF-β signaling pathways and was characterized by 5-LO nuclear envelope translocation with enhanced LTB4 production. This study offers one explanation of how an environmental injury unleashes the destructive potential of an otherwise-silent genetic mutation.

  View details for DOI 10.1161/CIRCULATIONAHA.119.040629

  View details for PubMedID 31462075

• Endothelial HIF-2alpha is Required for the Maintenance of Airway Microvasculature. Circulation Jiang, X., Tian, W., Tu, A. B., Pasupneti, S., Shuffle, E., Dahms, P., Zhang, P., Cai, H., Dinh, T. T., Liu, B., Cain, C., Giaccia, A. J., Butcher, E. C., Simon, C., Semenza, G. L., Nicolls, M. R. 2018

  Abstract

  BACKGROUND: Hypoxia-inducible factors (HIFs), especially HIF-1alpha and HIF-2alpha, are key mediators of the adaptive response to hypoxic stress and play essential roles in maintaining lung homeostasis. Human and animal genetics studies confirm that abnormal HIF correlates with pulmonary vascular pathology and chronic lung diseases, but it remains unclear whether endothelial cell (EC) HIF production is essential for microvascular health. The large airway has an ideal circulatory bed for evaluating histologic changes and physiology in genetically-modified rodents.METHODS: The tracheal microvasculature of mice, with conditionally-deleted or overexpressed HIF-1alpha or HIF-2alpha, was evaluated for anatomy, perfusion, and permeability. Angiogenic signaling studies assessed vascular changes attributable to dysregulated HIF expression. An orthotopic tracheal transplantation model further evaluated the contribution of individual HIF isoforms in airway ECs.RESULTS: The genetic deletion of Hif-2alpha, but not Hif-1alpha, caused tracheal EC apoptosis, diminished pericyte coverage, reduced vascular perfusion, defective barrier function, overlying epithelial abnormalities and subepithelial fibrotic remodeling. HIF-2alpha promoted microvascular integrity in airways through endothelial angiopoietin-1/TIE2 signaling and Notch activity. In functional tracheal transplants, HIF-2alpha deficiency in airway donors accelerated graft microvascular loss, whereas HIF-2alpha or angiopoietin-1 overexpression prolonged transplant microvascular perfusion. Augmented endothelial HIF-2alpha in transplant donors promoted airway microvascular integrity and diminished alloimmune inflammation.CONCLUSIONS: Our findings reveal that the constitutive expression of endothelial HIF-2alpha is required for airway microvascular health.

  View details for PubMedID 30586708

• Microhemorrhage-associated tissue iron enhances the risk forAspergillus fumigatusinvasion in a mouse model of airway transplantation. Science translational medicine Hsu, J. L., Manouvakhova, O. V., Clemons, K. V., Inayathullah, M. n., Tu, A. B., Sobel, R. A., Tian, A. n., Nazik, H. n., Pothineni, V. R., Pasupneti, S. n., Jiang, X. n., Dhillon, G. S., Bedi, H. n., Rajadas, J. n., Haas, H. n., Aurelian, L. n., Stevens, D. A., Nicolls, M. R. 2018; 10 (429)

  Abstract

  Invasive pulmonary disease due to the moldAspergillus fumigatuscan be life-threatening in lung transplant recipients, but the risk factors remain poorly understood. To study this process, we used a tracheal allograft mouse model that recapitulates large airway changes observed in patients undergoing lung transplantation. We report that microhemorrhage-related iron content may be a major determinant ofA. fumigatusinvasion and, consequently, its virulence. Invasive growth was increased during progressive alloimmune-mediated graft rejection associated with high concentrations of ferric iron in the graft. The role of iron inA. fumigatusinvasive growth was further confirmed by showing that this invasive phenotype was increased in tracheal transplants from donor mice lacking the hemochromatosis gene (Hfe -/- ). The invasive phenotype was also increased in mouse syngrafts treated with topical iron solution and in allograft recipients receiving deferoxamine, a chelator that increases iron bioavailability to the mold. The invasive growth of the iron-intolerantA. fumigatusdouble-knockout mutant (ΔsreA/ΔcccA) was lower than that of the wild-type mold. Alloimmune-mediated microvascular damage and iron overload did not appear to impair the host's immune response. In human lung transplant recipients, positive staining for iron in lung transplant tissue was more commonly seen in endobronchial biopsy sections from transplanted airways than in biopsies from the patients' own airways. Collectively, these data identify iron as a major determinant ofA. fumigatusinvasive growth and a potential target to treat or preventA. fumigatusinfections in lung transplant patients.

  View details for PubMedID 29467298

• Combined heart lung transplantation: an updated review of the current literature. Transplantation Pasupneti, S., Dhillon, G., Reitz, B., Khush, K. 2017

  Abstract

  Heart lung transplantation is a viable treatment option for patients with many end stage heart and lung pathologies. However, given the complex nature of the procedure, it is imperative that patients are selected appropriately and the clinician is aware of the many unique aspects in management of this population. This review seeks to describe updated organ selection policies, peri and postoperative management strategies, monitoring of graft function, and clinical outcomes for patients following combined heart-lung transplantation in the current era.

  View details for DOI 10.1097/TP.0000000000001820

  View details for PubMedID 28505026

• Aspergillus-related pulmonary diseases in lung transplantation MEDICAL MYCOLOGY Pasupneti, S., Manouvakhova, O., Nicolls, M. R., Hsu, J. L. 2017; 55 (1): 96-102

  Abstract

  While lung transplantation is an attractive treatment option for many end stage lung diseases, the relatively high 5-year mortality continues to be a significant limiting factor. Among the foremost reasons for this is the eventual development of obstructive chronic lung allograft dysfunction. Infections, which the lung allograft is especially prone to, are a major risk factor. Specifically, the Aspergillus species cause a higher burden of disease among lung transplant recipients, due to unique risk factors, such as relative hypoxemia. However, these risk factors also provide unique opportunities for treatment and preventative strategies, as outlined in this review.

  View details for DOI 10.1093/mmy/myw121

  View details for Web of Science ID 000393896500013

• Lung transplantation following death by drowning: a review of the current literature. Clinical transplantation Pasupneti, S., Patel, K., Mooney, J. J., Chhatwani, L., Dhillon, G., Weill, D. 2016; 30 (10): 1195-1197

  Abstract

  While multiple donor characteristics have been cited as ideal for lung transplantation, there are minimal widely accepted exclusion criteria. One criterion that many centers view with hesitation is death by drowning. However, recent literature suggests such donors may result in acceptable outcomes following transplation. This review highlights a case of a patient who underwent successful bilateral lung transplant from a donor following a drowning event. A review of the current literature is presented, concluding with a new proposed set of favorable donor criteria following death by drowning. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1111/ctr.12822

  View details for PubMedID 27447443

• Elevated Troponin? Take Heart and Reconsider! CIRCULATION-HEART FAILURE Pasupneti, S., Khush, K. 2016; 9 (6)

  View details for DOI 10.1161/CIRCHEARTFAILURE.116.003237

  View details for Web of Science ID 000378139000014

  View details for PubMedID 27329986

  View details for PubMedCentralID PMC4918512

• Central venous catheters: incidence and predictive factors of venous thrombosis CLINICAL NEPHROLOGY Hammes, M., Desai, A., Pasupneti, S., Kress, J., Funaki, B., Watson, S., Herlitz, J., Hines, J. 2015; 84 (1): 21-28

  Abstract

  Central venous catheter access in an acute setting can be a challenge given underlying disease and risk for venous thrombosis. Peripherally inserted central venous catheters (PICCs) are commonly placed but limit sites for fistula creation in patients with chronic renal failure (CKD). The aim of this study is to determine the incidence of venous thrombosis from small bore internal jugular (SBIJ) and PICC line placement. This investigation identifies populations of patients who may not be ideal candidates for a PICC and highlights the importance of peripheral vein preservation in patients with renal failure.A venous Doppler ultrasound was performed at the time of SBIJ insertion and removal to evaluate for thrombosis in the internal jugular vein. Data was collected pre- and post-intervention to ascertain if increased vein preservation knowledge amongst the healthcare team led to less use of PICCs. Demographic factors were collected in the SBIJ and PICC groups and risk factor analysis was completed.1,122 subjects had PICC placement and 23 had SBIJ placement. The incidence of thrombosis in the PICC group was 10%. One patient with an SBIJ had evidence of central vein thrombosis when the catheter was removed. Univariate and multivariate analysis demonstrated a history of transplant, and the indication of total parenteral nutrition was associated with thrombosis (p<0.001). The decrease in PICCs placed in patients with CKD 6 months before and after intervention was significant (p<0.05).There are subsets of patients ith high risk for thrombosis who may not be ideal candidates for a PICC.

  View details for DOI 10.5414/CN108347

  View details for Web of Science ID 000364530900003

  View details for PubMedID 25997503

  View details for PubMedCentralID PMC4750112

• Initial Commitment to Pre-Exposure Prophylaxis and Circumcision for HIV Prevention amongst Indian Truck Drivers PLOS ONE Schneider, J. A., Dandona, R., Pasupneti, S., Lakshmi, V., Liao, C., Yeldandi, V., Mayer, K. H. 2010; 5 (7)

  Abstract

  Studies of HIV prevention interventions such as pre-exposure prophylaxis (PREP) and circumcision in India are limited. The present study sought to investigate Indian truck-drivers initial commitment to PREP and circumcision utilizing the AIDS Risk Reduction Model. Ninety truck-drivers completed an in-depth qualitative interview and provided a blood sample for HIV and HSV-2 testing. Truck-drivers exhibited low levels of initial commitment towards PREP and even lower for circumcision. However, potential leverage points for increasing commitment were realized in fear of infecting family rather than self, self-perceptions of risk, and for PREP focusing on cultural beliefs towards medication and physicians. Cost was a major barrier to both HIV prevention interventions. Despite these barriers, our findings suggest that the ARRM may be useful in identifying several leverage points that may be used by peers, health care providers and public health field workers to enhance initial commitment to novel HIV prevention interventions in India.

  View details for DOI 10.1371/journal.pone.0011922

  View details for Web of Science ID 000280520300031

  View details for PubMedID 20689602

  View details for PubMedCentralID PMC2912853