In the past 20 years, it has become apparent that inflammation is a fundamental driver of WHO Group 1 pulmonary arterial hypertension (PAH), in such diverse etiologies as idiopathic, collagen vascular disease- associated (CVD-PAH), and infection-associated disease, notably of schistosomiasis-associated PAH, and Group 3 COPD-related pulmonary hypertension (PH). Our work has delineated the upstream role of Type 2 inflammation triggered by Schistosoma eggs in the lung circulation, leading to TGF-? production, which drives subsequent pulmonary vascular remodeling and PH in Schistosoma-induced PH. Specifically, Project 2 addresses the key role of TH2 inflammation, leading to macrophage activation of TGF-?, as the bridge between Type 2 inflammation and molecular effectors of pulmonary vascular remodeling. Building on extensive and innovative experimental and human studies, Project 2 complements the insights into STAT3-driven hypoxia-driven stimuli in Project 1; furthermore, with Project 3, we expand on the role of leukotriene B4 (LTB4) in Schistosoma-PH. Our work is novel not only in regards to linking inflammation and pulmonary hypertension, but also in leveraging the importance of schistosomiasis as the third most common parasitic disease worldwide, and one of the most common causes of WHO Group 1 PAH, affecting approximately 5-15 million people predominantly in Africa and Brazil, with a similar spectrum of pulmonary vascular lesions as IPAH and CVD-PAH. We propose that schistosomiasis-induced Type 2 immune responses trigger TGF-?1 synthesis and activation by macrophages, via the direction action of macrophage-derived thrombospondin (TSP-1). Active TGF-?1 then causes metabolic reprogramming of vascular cells, resulting in pulmonary vascular remodeling and pulmonary hypertension.
Our specific aims are:
Aim 1 : To determine that the Type 2 inflammatory mediators IL-4 and IL-13 drive pro-vascular remodeling macrophages.
Aim 2 : To determine that IL-4/IL-13-stimulated macrophages induce vascular remodeling by TGF-?1 activation via direct interaction with TSP-1.
Aim 3 : To determine that macrophage-driven TGF-?1 causes metabolic reprogramming in pulmonary vascular cells in Schistosoma-induced PH. This proposal relies on the integration of genetically modified mouse models of Schistosoma-PH with parallel analysis of diseased human lung tissue, including both Schistosoma- and scleroderma-associated PAH. Complementary and synergistic lines of investigations are proposed to determine if key mechanistic elements of Project 2 also are also pertinent in Projects 1 (specifically the roles of adventitia fibroblasts and STAT- specific macrophages populations) and 3 (proremodeling action of LTB4). Focused retrospective studies aimed at targets of Type 2 inflammation are leveraged with Clinical Core B to translate key findings into PAH patients.
Inflammation is a fundamental driver of pulmonary arterial hypertension (PAH) due to multiple causes. We have worked to elucidate the mechanism for the development of this condition after infection with Schistosoma, a parasite that is a major cause of PAH worldwide, primarily in Brazil, Africa, the Middle East, and South Asia. Our project proposes to study how activation of the immune system in this context results in changes in the lung blood vessels, resulting in this vascular disease.
|Jiang, Xinguo; Nicolls, Mark R; Tian, Wen et al. (2018) Lymphatic Dysfunction, Leukotrienes, and Lymphedema. Annu Rev Physiol 80:49-70|
|Schäfer, Michal; Humphries, Stephen; Stenmark, Kurt R et al. (2018) 4D-flow cardiac magnetic resonance-derived vorticity is sensitive marker of left ventricular diastolic dysfunction in patients with mild-to-moderate chronic obstructive pulmonary disease. Eur Heart J Cardiovasc Imaging 19:415-424|
|D'Alessandro, Angelo; El Kasmi, Karim C; Plecitá-Hlavatá, Lydie et al. (2018) Hallmarks of Pulmonary Hypertension: Mesenchymal and Inflammatory Cell Metabolic Reprogramming. Antioxid Redox Signal 28:230-250|
|Karoor, Vijaya; Fini, Mehdi A; Loomis, Zoe et al. (2018) Sustained Activation of Rho GTPases Promotes a Synthetic Pulmonary Artery Smooth Muscle Cell Phenotype in Neprilysin Null Mice. Arterioscler Thromb Vasc Biol 38:154-163|
|Stenmark, Kurt R; Graham, Brian B (2018) Urocortin 2: will a drug targeting both the vasculature and the right ventricle be the future of pulmonary hypertension therapy? Cardiovasc Res 114:1057-1059|
|Madhavan, Krishna; Frid, Maria G; Hunter, Kendall et al. (2018) Development of an electrospun biomimetic polyurea scaffold suitable for vascular grafting. J Biomed Mater Res B Appl Biomater 106:278-290|
|Stenmark, Kurt R; Frid, Maria G; Graham, Brian B et al. (2018) Dynamic and diverse changes in the functional properties of vascular smooth muscle cells in pulmonary hypertension. Cardiovasc Res 114:551-564|
|Schäfer, Michal; Kheyfets, Vitaly O; Barker, Alex J et al. (2018) Reduced shear stress and associated aortic deformation in the thoracic aorta of patients with chronic obstructive pulmonary disease. J Vasc Surg 68:246-253|
|Graham, Brian B; Kumar, Rahul; Mickael, Claudia et al. (2018) Vascular Adaptation of the Right Ventricle in Experimental Pulmonary Hypertension. Am J Respir Cell Mol Biol 59:479-489|
|Wick, Marilee J; Harral, Julie W; Loomis, Zoe L et al. (2018) An Optimized Evans Blue Protocol to Assess Vascular Leak in the Mouse. J Vis Exp :|
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