It is well established that exposure of experimental animals to hundred percent oxygen for longer than 48 hours results in adverse alterations of lung structure and function. It is the objective of this project to use an isolated perfused rat lung preparation to assess changes in lung metabolic function that occur prior to observable alterations in pathology. Based on previous studies demonstrating early oxygen-induced impairment of lung pyruvate metabolism, the specific hypothesis that oxygen inactivation of mitochondrial enzymes results from failure of cellular anti-oxidant defense mechanisms, is to be tested by the following specific aims. The effects of oxygen on lung mitochondrial function will be determined by measurement of changes in perfused lung fatty acid metabolism, pyruvate dehydrogenase activity and oxidation of cytosolic reducing equivalents following in vivo exposures to 100% oxygen. The possible mechanisms of mitochondrial impairment will be investigated by measurements of metabolic function in the presence of specific inhibitors of lung anti-oxidant defense mechanisms. Differences in the way endothelial and epithelial cells are affected by oxygen will be determined by measurements of changes in isolated cell metabolic function when exposed in vitro to oxygen. Possible protective effects of pretreatment with heterocyclic urea compounds, that increase lung superoxide dismutase and catalase activities, will be assessed in pretreated perfused lungs and cultured cells by measuring changes in the sensitivity of metabolic functions to the adverse effects of oxygen-exposure. In order to establish the possible role of polymorphonuclear leukocytes (PMNs) in oxygen-induced lung injury and to correlate early injury with enhanced PMN adherence, metabolic functions will be assessed in isolated lungs and endothelial cells exposed to oxygen in the presence of PMNs. These studies will provide a better understanding of the early biochemical events that lead to oxygen toxicity, and so provide the basis for the future development of protective interventions when oxygen has to be used to treat severe hypoxemia resulting from respiratory failure and acute lung injury.
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