Pulmonary Vascular Research Institute

Kerala, India

Pulmonary Vascular Research Institute

Kerala, India
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Gaskill C.F.,Vanderbilt University | Carrier E.J.,Vanderbilt University | Kropski J.A.,Vanderbilt University | Bloodworth N.C.,Vanderbilt University | And 15 more authors.
Journal of Clinical Investigation | Year: 2017

Pulmonary vascular disease is characterized by remodeling and loss of microvessels and is typically attributed to pathological responses in vascular endothelium or abnormal smooth muscle cell phenotypes. We have challenged this understanding by defining an adult pulmonary mesenchymal progenitor cell (MPC) that regulates both microvascular function and angiogenesis. The current understanding of adult MPCs and their roles in homeostasis versus disease has been limited by a lack of genetic markers with which to lineage label multipotent mesenchyme and trace the differentiation of these MPCs into vascular lineages. Here, we have shown that lineage-labeled lung MPCs expressing the ATP-binding cassette protein ABCG2 (ABCG2+) are pericyte progenitors that participate in microvascular homeostasis as well as adaptive angiogenesis. Activation of Wnt/β-catenin signaling, either autonomously or downstream of decreased BMP receptor signaling, enhanced ABCG2+ MPC proliferation but suppressed MPC differentiation into a functional pericyte lineage. Thus, enhanced Wnt/β-catenin signaling in ABCG2+ MPCs drives a phenotype of persistent microvascular dysfunction, abnormal angiogenesis, and subsequent exacerbation of bleomycin-induced fibrosis. ABCG2+ MPCs may, therefore, account in part for the aberrant microvessel function and remodeling that are associated with chronic lung diseases.


Graham B.B.,University of Colorado at Denver | Graham B.B.,Pulmonary Vascular Research Institute | Kumar R.,University of Colorado at Denver | Kumar R.,Pulmonary Vascular Research Institute
Pulmonary Circulation | Year: 2014

Inflammation is associated with multiple forms of pulmonary arterial hypertension (PAH), including autoimmune (scleroderma) and infectious (HIV, schistosomiasis) etiologies. More than 200 million people worldwide are infected with Schistosoma, predominantly in Brazil, Africa, the Middle East, and South Asia. Schistosomiasis causes PAH in about 6.1% of those chronically infected and is particularly associated with the species Schistosoma mansoni. Treatment for schistosomiasis-associated PAH includes antihelminthic treatment, if active infection is present (although associated with little immediate benefit to the pulmonary hypertension), and then pharmacologic treatment with targeted pulmonary vascular therapies, including phosphodiesterase type 5 inhibitors and endothelin receptor antagonists. The pathophysiological mechanism by which this parasitic infection causes pulmonary hypertension is unknown but is unlikely to be simple mechanical obstruction of the pulmonary vasculature by parasite eggs. Preexisting hepatosplenic disease due to Schistosoma infection is likely important because of portopulmonary hypertension and/or because it allows egg embolization to the lung by portocaval shunts. Potential immune signaling originating in the periegg granulomas causing the pulmonary vascular disease includes the cytokines interleukin (IL)-4, IL-6, IL-13, and transforming growth factor β. Modulating these pathways may be possible targets for future therapy of schistosomiasis-associated PAH specifically, and study of this disease may provide novel insights into other inflammatory causes of PAH. © 2014 by the Pulmonary Vascular Research Institute. All rights reserved.


Chabon J.J.,University of Colorado at Denver | Gebreab L.,University of Colorado at Denver | Kumar R.,University of Colorado at Denver | Debella E.,University of Colorado at Denver | And 9 more authors.
Pulmonary Circulation | Year: 2014

There is significant evidence that Th2 (T helper 2)-mediated inflammation supports the pathogenesis of both human and experimental animal models of pulmonary hypertension (PH). A key immune regulator is vascular endothelial growth factor (VEGF), which is produced by Th2 inflammation and can itself contribute to Th2 pulmonary responses. In this study, we interrogated the role of VEGF signaling in a murine model of schistosomiasis-induced PH with a phenotype of significant intrapulmonary Th2 inflammation, vascular remodeling, and elevated right ventricular pressures. We found that VEGF receptor blockade partially suppressed the levels of the Th2 inflammatory cytokines interleukin (IL)-4 and IL-13 in both the lung and the liver after Schistosoma mansoni exposure and suppressed pulmonary vascular remodeling. These findings suggest that VEGF positively contributes to schistosomiasis-induced vascular inflammation and remodeling, and they also provide evidence for a VEGF-dependent signaling pathway necessary for pulmonary vascular remodeling and inflammation in this model. © 2014 by the Pulmonary Vascular Research Institute. All rights reserved.


Graham B.B.,University of Colorado at Denver | Graham B.B.,Pulmonary Vascular Research Institute | Chabon J.,University of Colorado at Denver | Gebreab L.,University of Colorado at Denver | And 19 more authors.
Circulation | Year: 2013

BACKGROUND-: The pathogenic mechanisms underlying pulmonary arterial hypertension resulting from schistosomiasis, one of the most common causes of pulmonary hypertension worldwide, remain unknown. We hypothesized that transforming growth factor-β (TGF-β) signaling as a consequence of Th2 inflammation is critical for the pathogenesis of this disease. METHODS AND RESULTS-: Mice sensitized and subsequently challenged with Schistosoma mansoni eggs developed pulmonary hypertension associated with an increase in right ventricular systolic pressure, thickening of the pulmonary artery media, and right ventricular hypertrophy. Rho-kinase-dependent vasoconstriction accounted for ≈60% of the increase in right ventricular systolic pressure. The pulmonary vascular remodeling and pulmonary hypertension were dependent on increased TGF-β signaling, as pharmacological blockade of the TGF-β ligand and receptor, and mice lacking Smad3 were significantly protected from Schistosoma-induced pulmonary hypertension. Blockade of TGF-β signaling also led to a decrease in interleukin-4 and interleukin-13 concentrations, which drive the Th2 responses characteristic of schistosomiasis lung pathology. Lungs of patients with schistosomiasis-associated pulmonary arterial hypertension have evidence of TGF-β signaling in their remodeled pulmonary arteries. CONCLUSION-: Experimental S mansoni-induced pulmonary vascular disease relies on canonical TGF-β signaling. © 2013 American Heart Association, Inc.


Kolosionek E.,University of Kent | Kolosionek E.,Pulmonary Vascular Research Institute | Crosby A.,Pulmonary Vascular Research Institute | Crosby A.,University of Cambridge | And 5 more authors.
Expert Review of Anti-Infective Therapy | Year: 2010

In this article we focus on the pathogenesis and clinical characteristics of schistosomiasis infection on the lung vasculature. Overall, the basic biology and understanding of Schistosoma immune responses and their effect on the cardiopulmonary system is limited in both animal and human models, which hinders clinical care and drug development. The inflammatory response to the eggs in the lung appears to contribute to the remodeling of the pulmonary vessels. Portal hypertension caused by parasitemia also appears to contribute to the development of pathophysiologic alterations of the pulmonary vascular bed. Antischistosomal therapy, praziquantel, used for pulmonary hypertension secondary to schistosomiasis usually has no effect, but it is given to prevent further progression of disease. Currently, there are no clinical trials for the treatment of pulmonary vascular disease secondary to schistosomiasis. Specialty drugs such as phosphodiesterase type 5 or tyrosine kinase inhibitors exhibit some interesting activity, yet are prohibitively expensive, lack safety and efficacy studies in schistosomiasis endemic populations, and tend to be limited by safety, efficacy, route of administration and compliance problems. © 2010 Expert Reviews Ltd.


Qadar Pasha M.A.,Institute of Genomics and Integrative Biology | Qadar Pasha M.A.,Pulmonary Vascular Research Institute | Newman J.H.,Vanderbilt University | Newman J.H.,Pulmonary Vascular Research Institute
Chest | Year: 2010

Globally, it is estimated that > 140 million people live at a high altitude (HA), defined as > 2,500 m (8,200 ft), and that countless others sojourn to the mountains for work, travel, and sport. The distribution of exposure to HA is worldwide, including 35 million in the Andes and > 80 million in Asia, including China and central Asia. HA stress primarily is due to the hypoxia of low atmospheric pressure, but dry air, intense solar radiation, extreme cold, and exercise contribute to acute and chronic disorders. The acute disorders are acute mountain sickness (also known as soroche), HA cerebral edema, and HA pulmonary edema (HAPE). Of these, HAPE is highly correlated with acute pulmonary hypertension. The first chronic syndrome described in HA dwellers in Peru was chronic mountain sickness (Monge disease), which has a large component of relative hypoventilation and secondary erythrocytosis. The prevalence of chronic mountain sickness in HA dwellers ranges from 1.2% in native Tibetans to 5.6% in Chinese Han; 6% to 8% in male residents of La Paz, Bolivia; and 15.6% in the Andes. Subacute mountain sickness is an exaggerated pulmonary hypertensive response to HA hypoxia occurring over months, most often in infants and very young children. Chronic pulmonary hypertension with heart failure but without hypoventilation is seen in Asia. Not only does HA pulmonary hypertension exact health consequences for the millions affected, but also the mechanisms of disease relate to pulmonary hypertension associated with multiple other disorders. Genetic understanding of these disorders is in its infancy. © 2010 American College of Chest Physicians.


Graham B.B.,University of Colorado at Denver | Graham B.B.,Pulmonary Vascular Research Institute | Bandeira A.P.,University of Pernambuco | Bandeira A.P.,Pulmonary Vascular Research Institute | And 6 more authors.
Chest | Year: 2010

Inflammation is likely a critical underlying etiology in many forms of severe pulmonary hypertension (PH), and schistosomiasis-associated PH, one of the most common causes of PH worldwide, is likely driven by the host response to parasite antigens. More than 200 million people are infected with schistosomiasis, the third most common parasitic disease, and approximately 1% of those chronically infected develop PH. Acute cutaneous infection causes inflammation at the site of parasite penetration followed by a subacute immune complex-mediated hypersensitivity response as the parasite migrates through the lungs. Chronic schistosomiasis infection induces a granulomatous inflammation around ova deposited in the tissue. In particular, Schistosoma mansoni migrates to the portal venous system and causes preportal fibrosis in a subset of individuals and appears to be a prerequisite for PH. Portal hypertension facilitates shunting of ova from the portal system to the pulmonary arterial tree, resulting in localized periovular pulmonary granulomas. The pulmonary vascular remodeling is likely a direct consequence of the host inflammatory response, and portopulmonary hypertension may be a significant contributor. New specific therapies available for PH have not been widely tested in patients with schistosomiasis and often are unavailable for those infected in resource-poor areas of the world where schistosomiasis is endemic. Furthermore, the current PH therapies in general target vasodilation rather than vascular remodeling and inflammation. Further research is needed into the pathogenic mechanism by which this parasitic infection results in pulmonary vascular remodeling and PH, which also may be informative regarding the etiology of other types of PH. © 2010 American College of Chest Physicians.


West J.D.,Vanderbilt University | West J.D.,Vanderbilt Vascular Biology Center | Austin E.D.,Vanderbilt University | Gaskill C.,Vanderbilt University | And 32 more authors.
American Journal of Physiology - Cell Physiology | Year: 2014

Understanding differences in gene expression that increase risk for pulmonary arterial hypertension (PAH) is essential to understanding the molecular basis for disease. Previous studies on patient samples were limited by end-stage disease effects or by use of nonadherent cells, which are not ideal to model vascular cells in vivo. These studies addressed the hypothesis that pathological processes associated with PAH may be identified via a genetic signature common across multiple cell types. Expression array experiments were initially conducted to analyze cell types at different stages of vascular differentiation (mesenchymal stromal and endothelial) derived from PAH patient-specific induced pluripotent stem (iPS) cells. Molecular pathways that were altered in the PAH cell lines were then compared with those in fibroblasts from 21 patients, including those with idiopathic and heritable PAH. Wnt was identified as a target pathway and was validated in vitro using primary patient mesenchymal and endothelial cells. Taken together, our data suggest that the molecular lesions that cause PAH are present in all cell types evaluated, regardless of origin, and that stimulation of the Wnt signaling pathway was a common molecular defect in both heritable and idiopathic PAH. © 2014 the American Physiological Society.


Fijalkowska I.,Johns Hopkins University | Xu W.,Cleveland Clinic | Comhair S.A.A.,Cleveland Clinic | Janocha A.J.,Cleveland Clinic | And 9 more authors.
American Journal of Pathology | Year: 2010

Severe pulmonary hypertension is irreversible and often fatal. Abnormal proliferation and resistance to apoptosis of endothelial cells (ECs) and hypertrophy of smooth muscle cells in this disease are linked to decreased mitochondria and preferential energy generation by glycolysis. We hypothesized this metabolic shift of pulmonary hypertensive ECs is due to greater hypoxia inducible-factor1α (HIF-1α) expression caused by low levels of nitric oxide combined with low superoxide dismutase activity. We show that cultured ECs from patients with idiopathic pulmonary arterial hypertension (IPAH-ECs) have greater HIF-1α expression and transcriptional activity than controls under normoxia or hypoxia, and pulmonary arteries from affected patients have increased expression of HIF-1α and its target carbonic anhydrase IX. Decreased expression of manganese superoxide dismutase (MnSOD) in IPAH-ECs paralleled increased HIF-1α levels and small interfering (SI) RNA knockdown of MnSOD, but not of the copper-zinc SOD, increased HIF-1 protein expression and hypoxia response element (HRE)-driven luciferase activity in normoxic ECs. MnSOD siRNA also reduced nitric oxide production in supernatants of IPAH-ECs. Conversely, low levels of a nitric oxide donor reduced HIF-1α expression in normoxic IPAH-ECs. Finally, mitochondria numbers increased in IPAH-ECs with knockdown of HIF-1α. These findings indicate that alterations of nitric oxide and MnSOD contribute to pathological HIF-1α expression and account for lower numbers of mitochondria in IPAH-ECs. Copyright © American Society for Investigative Pathology.

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