Heme Oxygenase-1 in Lung Ischemia-Reperfusion Injury

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DESCRIPTION (provided by applicant): Oxidant injury is a major contributor to the pathogenesis of many disease processes including acute lung injury. Anoxia-reoxygenation (A-R) In cells and ilschemia-reperfusion (I-R) in lungs are common models of oxidant injury. Lung I-R is likely the inciting injury during lung transplantation/surgery, thromboembolectomy, pulmonary embolism, and re-expansion pulmonary edema. These disorders have high mortalities with limited therapeutic options. This is largely due to our limited knowledge of underlying pathogenesis. We also lack appreciation of the degree to which regulatory events in vitro (A-R) are predictive of the events in vivo (I-R). Heme oxygenase (HO) catalyzes the initial and rate-limiting step in the oxidative degradation of heme to biliverdin with generation of carbon monoxide (CO) and iron. A variety of oxidant stressors strongly induce expression of HO-1, an inducible isoform of HO. Studies from our laboratory and others have demonstrated that HO-1 can protect against oxidant-induced lung injury. However, the ability of HO-1 to confer protection and the processes regulating its production in this setting has not been adequately addressed. In addition, the pivotal cell-type responsible for HO-1-mediated protection against oxidant lung injury is unknown. To begin to understand the processes that regulate A-R/I-R we examined the effects of HO-1 in these injury models. We have demonstrated that HO-1 is markedly induced in endothelial cells and mouse lung after A-R/I-R. In addition, the mitogen-activated protein kinases (MAPKs) are responsible for A-R-induced HO-1 expression. We now show that HO-1 overexpression significantly diminishes A-R/I-R-induced apoptosis in cultured lung endothelial cells and in mouse lung. Our data has led us to propose the following hypotheses: 1) in A-R, HO-1 is induced via novel activation pathways that involve MAPKs and cooperative transcription factor interactions; 2) in I-R, similar pathways are activated and are cytoprotective; and 3) in I-R, p38 MAPK activation of endothelial cell HO-1 is a critical event in cytoprotection. To test these hypotheses we will: 1) characterize the cis- and trans-acting elements that mediate HO-1 induction and define the consequences in vitro; 2) determine whether A-R regulates the relevant transcription factors via p38 or JNK MAPKs and define the consequences in vitro; 3) determine whether the processes identified in Aims I and 2 are important in vivo; and 4) define the role of endothelial cell p38 MAPK and HO-1 in HO-1-mediated cytoprotection in vivo.