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.
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.
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