All Publications


  • A Dominant Role for Regulatory T Cells in Protecting Females Against Pulmonary Hypertension. Circulation research Tamosiuniene, R. n., Manouvakhova, O. n., Mesange, P. n., Saito, T. n., Qian, J. n., Sanyal, M. n., Lin, Y. C., Nguyen, L. P., Luria, A. n., Tu, A. B., Sante, J. M., Rabinovitch, M. n., Fitzgerald, D. J., Graham, B. B., Habtezion, A. n., Voelkel, N. F., Aurelian, L. n., Nicolls, M. R. 2018

    Abstract

    Rationale: Pulmonary arterial hypertension (PH) is a life-threatening condition associated with immune dysregulation and abnormal regulatory T cell (Treg) activity, but it is currently unknown whether and how abnormal Treg function differentially affects males and females. Objective: To evaluate whether and how Treg-deficiency differentially affects male and female rats in experimental PH. Methods and Results: Male and female athymicrnu/rnurats, lacking Tregs, were treated with the vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor SU5416 or chronic hypoxia and evaluated for PH; some animals underwent Treg immune reconstitution (IR) before SU5416 administration. Plasma prostacyclin (PGI2) levels were measured. Lung and right ventricles (RVs) were assessed for the expression of the vasoprotective proteins cyclooxygenase-2 (COX-2), prostacyclin synthase (PTGIS), programmed death ligand-1 (PDL-1), and heme oxygenase-1 (HO-1). Inhibitors of these pathways were administered to athymic rats undergoing Treg IR. Finally, human cardiac microvascular endothelial cells co-cultured with Tregs were evaluated for COX-2, PDL-1, HO-1, and estrogen receptor (ER) expression, and culture supernatants were assayed for PGI2 and IL-10. SU5416-treatment and chronic hypoxia produced more severe PH in female than male athymic rats. Females were distinguished by greater pulmonary inflammation, augmented RV fibrosis, lower plasma PGI2 levels, decreased lung COX-2, PTGIS, HO-1 and PDL-1 expression and reduced RV PDL-1 levels. In both sexes, Treg IR protected against PH development and raised levels of plasma PGI2 and cardiopulmonary COX-2, PTGIS, PDL-1, and HO-1. Inhibiting COX-2, HO-1, and programmed death-1 (PD1)/PDL1 pathways abrogated Treg protection. In vitro, human Tregs directly upregulated endothelial COX-2, PDL1, HO-1, ERs and increased supernatant levels of PGI2 and IL-10. Conclusions: In two animal models of PH based on Treg deficiency, females developed more severe PH than males. The data suggest that females are especially reliant on normal Treg function to counteract the effects of pulmonary vascular injury leading to PH.

    View details for PubMedID 29545367

  • Leukotriene B-4 Activates Pulmonary Artery Adventitial Fibroblasts in Pulmonary Hypertension HYPERTENSION Qian, J., Tian, W., Jiang, X., Tamosiuniene, R., Sung, Y. K., Shuffle, E. M., Tu, A. B., Valenzuela, A., Jiang, S., Zamanian, R. T., Fiorentino, D. F., Voelkel, N. F., Peters-Golden, M., Stenmark, K. R., Chung, L., Rabinovitch, M., Nicolls, M. R. 2015; 66 (6): 1227-1239

    Abstract

    A recent study demonstrated a significant role for leukotriene B4 (LTB4) causing pulmonary vascular remodeling in pulmonary arterial hypertension. LTB4 was found to directly injure luminal endothelial cells and promote growth of the smooth muscle cell layer of pulmonary arterioles. The purpose of this study was to determine the effects of LTB4 on the pulmonary adventitial layer, largely composed of fibroblasts. Here, we demonstrate that LTB4 enhanced human pulmonary artery adventitial fibroblast proliferation, migration, and differentiation in a dose-dependent manner through its cognate G-protein-coupled receptor, BLT1. LTB4 activated human pulmonary artery adventitial fibroblast by upregulating p38 mitogen-activated protein kinase as well as Nox4-signaling pathways. In an autoimmune model of pulmonary hypertension, inhibition of these pathways blocked perivascular inflammation, decreased Nox4 expression, reduced reactive oxygen species production, reversed arteriolar adventitial fibroblast activation, and attenuated pulmonary hypertension development. This study uncovers a novel mechanism by which LTB4 further promotes pulmonary arterial hypertension pathogenesis, beyond its established effects on endothelial and smooth muscle cells, by activating adventitial fibroblasts.

    View details for DOI 10.1161/HYPERTENSIONAHA.115.06370

    View details for PubMedID 26558820

  • Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection AMERICAN JOURNAL OF TRANSPLANTATION Jiang, X., Nguyen, T. T., Tian, W., Sung, Y. K., Yuan, K., Qian, J., Rajadas, J., Sallenave, J., Nickel, N. P., Perez, V. d., RABINOVITCH, M., Nicolls, M. R. 2015; 15 (7): 1768-1781

    Abstract

    The loss of a functional microvascular bed in rejecting solid organ transplants is correlated with fibrotic remodeling and chronic rejection; in lung allografts, this pathology is predicted by bronchoalveolar fluid neutrophilia which suggests a role for polymorphonuclear cells in microcirculatory injury. In a mouse orthotopic tracheal transplant model, cyclosporine, which primarily inhibits T cells, failed as a monotherapy for preventing microvessel rejection and graft ischemia. To target neutrophil action that may be contributing to vascular injury, we examined the effect of a neutrophil elastase inhibitor, elafin, on the microvascular health of transplant tissue. We showed that elafin monotherapy prolonged microvascular perfusion and enhanced tissue oxygenation while diminishing the infiltration of neutrophils and macrophages and decreasing tissue deposition of complement C3 and the membrane attack complex, C5b-9. Elafin was also found to promote angiogenesis through activation of the extracellular signal-regulated kinase (ERK) signaling pathway but was insufficient as a single agent to completely prevent tissue ischemia during acute rejection episodes. However, when combined with cyclosporine, elafin effectively preserved airway microvascular perfusion and oxygenation. The therapeutic strategy of targeting neutrophil elastase activity alongside standard immunosuppression during acute rejection episodes may be an effective approach for preventing the development of irreversible fibrotic remodeling.

    View details for DOI 10.1111/ajt.13189

    View details for Web of Science ID 000356494300013

    View details for PubMedID 25727073

  • Graft microvascular disease in solid organ transplantation. Journal of molecular medicine (Berlin, Germany) Jiang, X., Sung, Y. K., Tian, W., Qian, J., Semenza, G. L., Nicolls, M. R. 2014; 92 (8): 797-810

    Abstract

    Alloimmune inflammation damages the microvasculature of solid organ transplants during acute rejection. Although immunosuppressive drugs diminish the inflammatory response, they do not directly promote vascular repair. Repetitive microvascular injury with insufficient regeneration results in prolonged tissue hypoxia and fibrotic remodeling. While clinical studies show that a loss of the microvascular circulation precedes and may act as an initiating factor for the development of chronic rejection, preclinical studies demonstrate that improved microvascular perfusion during acute rejection delays and attenuates tissue fibrosis. Therefore, preservation of a functional microvasculature may represent an effective therapeutic strategy for preventing chronic rejection. Here, we review recent advances in our understanding of the role of the microvasculature in the long-term survival of transplanted solid organs. We also highlight microvessel-centered therapeutic strategies for prolonging the survival of solid organ transplants.

    View details for DOI 10.1007/s00109-014-1173-y

    View details for PubMedID 24880953

  • Leukotrienes in pulmonary arterial hypertension. Immunologic research Tian, W., Jiang, X., Sung, Y. K., Qian, J., Yuan, K., Nicolls, M. R. 2014; 58 (2-3): 387-393

    Abstract

    Leukotrienes (LTs) are lipid mediators derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism and are markers and mediators of pulmonary inflammation. Research over the past two decades has established that LTs modulate inflammation in pulmonary arterial hypertension (PAH). The purpose of this review was to summarize the current knowledge of LTs in the pathophysiology of PAH and to highlight a recent study that advances our understanding of how leukotriene B4 (LTB4) specifically contributes to pulmonary vascular remodeling. The results of these studies suggest that pharmacological inhibition of LT pathways, especially LTB4, has high potential for the treatment of PAH.

    View details for DOI 10.1007/s12026-014-8492-5

    View details for PubMedID 24570092

  • Macrophages in solid organ transplantation. Vascular cell Jiang, X., Tian, W., Sung, Y. K., Qian, J., Nicolls, M. R. 2014; 6 (1): 5-?

    Abstract

    Macrophages are highly plastic hematopoietic cells with diversified functions related to their anatomic location and differentiation states. A number of recent studies have examined the role of macrophages in solid organ transplantation. These studies show that macrophages can induce allograft injury but, conversely, can also promote tissue repair in ischemia-reperfusion injury and acute rejection. Therapeutic strategies that target macrophages to improve outcomes in solid organ transplant recipients are being examined in preclinical and clinical models. In this review, we discuss the role of macrophages in different types of injury and rejection, with a focus on macrophage-mediated tissue injury, specifically vascular injury, repair and remodeling. We also discuss emerging macrophage-centered therapeutic opportunities in solid organ transplantation.

    View details for DOI 10.1186/2045-824X-6-5

    View details for PubMedID 24612731

  • Blocking Macrophage Leukotriene B-4 Prevents Endothelial Injury and Reverses Pulmonary Hypertension SCIENCE TRANSLATIONAL MEDICINE Tian, W., Jiang, X., Tamosiuniene, R., Sung, Y. K., Qian, J., Dhillon, G., Gera, L., Farkas, L., Rabinovitch, M., Zamanian, R. T., Inayathullah, M., Fridlib, M., Rajadas, J., Peters-Golden, M., Voelkel, N. F., Nicolls, M. R. 2013; 5 (200)

    Abstract

    Pulmonary hypertension (PH) is a serious condition that affects mainly young and middle-aged women, and its etiology is poorly understood. A prominent pathological feature of PH is accumulation of macrophages near the arterioles of the lung. In both clinical tissue and the SU5416 (SU)/athymic rat model of severe PH, we found that the accumulated macrophages expressed high levels of leukotriene A4 hydrolase (LTA4H), the biosynthetic enzyme for leukotriene B4 (LTB4). Moreover, macrophage-derived LTB4 directly induced apoptosis in pulmonary artery endothelial cells (PAECs). Further, LTB4 induced proliferation and hypertrophy of human pulmonary artery smooth muscle cells. We found that LTB4 acted through its receptor, BLT1, to induce PAEC apoptosis by inhibiting the protective endothelial sphingosine kinase 1 (Sphk1)-endothelial nitric oxide synthase (eNOS) pathway. Blocking LTA4H decreased in vivo LTB4 levels, prevented PAEC apoptosis, restored Sphk1-eNOS signaling, and reversed fulminant PH in the SU/athymic rat model of PH. Antagonizing BLT1 similarly reversed established PH. Inhibition of LTB4 biosynthesis or signal transduction in SU-treated athymic rats with established disease also improved cardiac function and reopened obstructed arterioles; this approach was also effective in the monocrotaline model of severe PH. Human plexiform lesions, one hallmark of PH, showed increased numbers of macrophages, which expressed LTA4H, and patients with connective tissue disease-associated pulmonary arterial hypertension exhibited significantly higher LTB4 concentrations in the systemic circulation than did healthy subjects. These results uncover a possible role for macrophage-derived LTB4 in PH pathogenesis and identify a pathway that may be amenable to therapeutic targeting.

    View details for Web of Science ID 000323705100010

  • Post-translational regulation of endothelial nitric oxide synthase in vascular endothelium FRONTIERS IN PHYSIOLOGY Qian, J., Fulton, D. 2013; 4

    Abstract

    Nitric oxide (NO) is a short-lived gaseous signaling molecule. In blood vessels, it is synthesized in a dynamic fashion by endothelial nitric oxide synthase (eNOS) and influences vascular function via two distinct mechanisms, the activation of soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP)-dependent signaling and the S-nitrosylation of proteins with reactive thiols (S-nitrosylation). The regulation of eNOS activity and NO bioavailability is critical to maintain blood vessel function. The activity of eNOS and ability to generate NO is regulated at the transcriptional, posttranscriptional, and posttranslational levels. Post-translational modifications acutely impact eNOS activity and dysregulation of these mechanisms compromise eNOS activity and foster the development of cardiovascular diseases (CVDs). This review will intergrate past and current literature on the post-translational modifications of eNOS in both health and disease.

    View details for DOI 10.3389/fphys.2013.00347

    View details for Web of Science ID 000346774000339

    View details for PubMedCentralID PMC3861784