Reperfusion of the ischemic intestine is associated with endothelial barrier dysfunction, and the reperfusion-induced loss of endothelial integrity has been shown to be mediated, in part, by oxidants. Some investigators have demonstrated that oxidant-induced endothelial cytotoxicity was potentiated by chemical hypoxia, suggesting the possibility that the postanoxic endothelium is predisposed to reoxygenation damage. Because anoxia compromises mitochondrial function and perturbs redox status, we hypothesize that athe predisposition of endothelial cells to reoxygenation injury is related to a dysregulation of postanoxic mitochondrial integrity and redox balance. We further hypothesize that postanoxic mitochondrial dysfunction is mediated by endothelial cell derived oxidants, is reversed by antioxidant supplementation, and can elicit an inflammatory response. The objectives of the current proposal are; (a) to characterize anoxia/reoxygenation-induced bioenergetic and redox changes (Aims 1 and 2) (b) to define these changes in terms of endothelial cell derived oxidant production (Aim 3) (c) to determine the role of exogenous antioxidants in preservation of mitochondrial integrity and redox balance (Aim 4). (d) to assess the impact of altered metabolic status on the molecular events associated with an inflammatory process (Aim 5). The overall strategy is to employ a combination of cellular, subcellular and molecular approaches to define the physiological and biochemical processes in A/R-mediated changes in endothelial cell redox balance and mitochondrial function and the influence of these changes on endothelial cell oxidant generation and the molecular events governing postanoxic leukocyte-endothelial cell interactions. The data will also provide information regarding the potential use of exogenous antioxidants in preserving metabolic integrity of the endothelium.

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