PULMONARY OXYGEN TOXICITY--MECHANISMS AND INTERVENTIONS

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The studies in this proposal are designed to provide insight into the fundamental mechanisms of pulmonary oxygen toxicity. The overall goal is to better understand the cell biological alterations responsible for the pulmonary surfactant system changes which occur in oxygen toxicity, and determine the efficacy of therapeutic interventions directed at the cellular level. Specific goals are (1) to assess changes in surfactant metabolism and energy status in type II pneumocytes isolated from rabbits during hyperoxic injury and recovery; (2) to use the oxygen toxicity model to determine mechanisms of coordinate regulation of surfactant metabolic functions; (3) to assess oxygen-induced changes in clearance of surfactant in vivo; (4) to determine whether there is a correlation between surfactant metabolism and cell proliferative ability; and (5) to determine the ability of antioxidants to prevent sublethal type II pneumocyte damage. These goals will be achieved by assessing basal level and stimulated surfactant synthesis, secretion, and re-uptake (of both phospholipids and apoproteins) during oxygen toxicity and recovery (in room air) using radiolabeled phospholipids and proteins. In addition, levels of ATP, NADH, NADPH will be assessed in these cells in conjunction with measurements of DNA strand nicks and ADP-ribosylation reactions. Type II cell proliferation during recovery from oxygen toxicity can be halted by administration of agents which inhibit polyamine synthesis, which will be used to determine whether inhibition of proliferation affects surfactant metabolism. Finally, delivery of sulfhydryl protective agents and other antioxidants to type II cells will be achieved by published methods of intratracheal delivery. The antioxidant augmented cells will then be analyzed to determine whether this therapeutic intervention ameliorates changes in surfactant metabolism during oxidant stress and these findings will be compared to the in vivo physiological efficacy of these treatments.