Tissue hypoxia is central to pathologic conditions such as myocardial ischemia and chronic lung disease. Hypoxia is a known primary or secondary stimulus for the development of pulmonary hypertension (PHtn). Various animal models exposed to hypoxia develop the pulmonary and cardiac manifestations characteristic of human disease. These include vasoconstriction and vessel wall remodeling with resultant right ventricular hypertrophy and ultimately lead to cardiac dysfunction and death. Despite significant progress in this area, the mechanisms underlying the development of PHtn are poorly understood and there is no cure for this disease. We have previously reported that an early transient inflammatory response in the lung precedes the development of hypoxic PHtn in mice and that targeted lung-specific, constitutive expression of the cytoprotective gene, heme oxygenase-1 (HO-1), prevents both the inflammatory response and the development of PHtn. In the previous grant period, we showed that NF-:B plays a central role in mediating hypoxia-induced lung inflammation and demonstrated that HO-1 inhibited the transactivation potential of NF-:B in vivo and prevented inflammation. In contrast, mice deficient in HO-1 manifest prolonged and sustained inflammation with right ventricular dilation and infarction. Using the tet-on system, we also generated a bitransgenic mouse model with inducible, lung-specific expression of HO-1. Using these mice, we demonstrate complete inhibition of hypoxia-induced lung inflammation when HO-1 levels are high in the presence of doxycycline (dox). Despite continued hypoxia, PHtn does not develop. Using in vitro models of hypoxia and in vivo models of disease, we aim to examine the cellular and molecular mechanisms by which HO-1 and its enzymatic products, bilirubin and CO, modulate inflammatory gene expression, lung inflammation, and vascular remodeling.
The specific aims of this proposal are: (1) to further characterize the role of inflammation in the development of hypoxic PHtn, (2) to examine the role of HO-1 in resolving hypoxic lung inflammation, and (3) to examine the mechanisms by which HO-1 modulates NF-:B transcriptional activity and regulates inflammatory cell function.

Public Health Relevance

Pulmonary hypertension is a serious disease that is often associated with common conditions, including infections, heart disease, or lung ailments whose underlying feature is chronic hypoxia. There is no cure for this disease. The study of the molecular, cellular, and pathophysiologic processes that underlie pulmonary hypertension is thus critical for the development of rational therapeutic strategies to prevent and treat this disorder.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Moore, Timothy M
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Children's Hospital Boston
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Willis, Gareth R; Kourembanas, Stella; Mitsialis, S Alex (2017) Toward Exosome-Based Therapeutics: Isolation, Heterogeneity, and Fit-for-Purpose Potency. Front Cardiovasc Med 4:63
Willis, Gareth R; Mitsialis, S Alex; Kourembanas, Stella (2017) ""Good things come in small packages"": application of exosome-based therapeutics in neonatal lung injury. Pediatr Res :
Mitsialis, S Alex; Kourembanas, Stella (2016) Stem cell-based therapies for the newborn lung and brain: Possibilities and challenges. Semin Perinatol 40:138-51
Kourembanas, Stella (2014) Expanding the pool of stem cell therapy for lung growth and repair. Circulation 129:2091-3
Hale, Andrew; Lee, Changjin; Annis, Sofia et al. (2014) An Argonaute 2 switch regulates circulating miR-210 to coordinate hypoxic adaptation across cells. Biochim Biophys Acta 1843:2528-42
Xiao, Yongguang; Christou, Helen; Liu, Li et al. (2013) Endothelial indoleamine 2,3-dioxygenase protects against development of pulmonary hypertension. Am J Respir Crit Care Med 188:482-91
Anversa, Piero; Perrella, Mark A; Kourembanas, Stella et al. (2012) Regenerative pulmonary medicine: potential and promise, pitfalls and challenges. Eur J Clin Invest 42:900-13
Hansmann, Georg; Fernandez-Gonzalez, Angeles; Aslam, Muhammad et al. (2012) Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension. Pulm Circ 2:170-81
Fernandez-Gonzalez, Angeles; Alex Mitsialis, S; Liu, Xianlan et al. (2012) Vasculoprotective effects of heme oxygenase-1 in a murine model of hyperoxia-induced bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 302:L775-84
Lee, Changjin; Mitsialis, S Alex; Aslam, Muhammad et al. (2012) Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation 126:2601-11

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