Cellular Responses to Hypoxia

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DESCRIPTION (provided by applicant): Tissue hypoxia is central to pathologic conditions such as myocardial ischemia and chronic lung disease. In the pulmonary vasculature, hypoxia causes vasoconstriction and vessel wall remodeling with resultant right ventricular hypertrophy. These pathophysiologic responses are the hallmark of pulmonary hypertension (PHTN). We and others have shown that hypoxia induces the expression of key smooth muscle cell mitogens and vasoconstrictors that play an important role in vessel wall remodeling in vivo. We have previously reported that hypoxia also increases the expression of heme oxygenase-1 (HO-1), a cytoprotective enzyme. HO-1 degrades heme to generate carbon monoxide (CO, a vasodilating gas that has anti-inflammatory properties), biliverdin (which is rapidly converted to the antioxidant bilirubin), and iron (sequestered by ferritin). Due to properties of HO-1 and its products, the consensus is that HO-1 may play an important role in protecting cells and tissues from hypoxia-induced injury. Studies by our group using HO-1 null (-/-) mice and transgenic mice with lung-specific HO-1 over expression support this hypothesis by showing that hypoxia produced right ventricular dilatation and infarction in all mice lacking HO-1 whereas mice with high lung HO-1 levels were protected from PHTN. Moreover, we noted that wild-type mice exposed to hypoxia developed marked lung inflammation with elevated expression of chemokines and cytokines as well as neutrophil infiltration prior to the manifestation of PHTN. Mice deficient in HO-1 had a more pronounced and sustained inflammatory response to hypoxia than wild-type controls whereas transgenic mice with high lung HO-1 levels manifested a complete absence of inflammation. The specific aims of this proposal are: A. To study the molecular mechanisms and signaling pathways by which hypoxia induces chemokine gene expression leading to lung inflammation. B. To investigate the mechanisms by which HO-1 inhibits inflammatory gene expression and vascular permeability induced by hypoxia. C. To determine whether inflammation plays a role in the development of hypoxic PHTN.