PREVENTION OF PULMONARY OXYGEN TOXICITY IN THE NEWBORN

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The objective of this work is to elucidate further the mechanisms involved in oxygen toxicity of the newborn and its prevention. Studies of the influence of antioxidants such as Vitamin E and the glutathione system on the metabolic and morphologic correlates of cellular oxygen toxicity will be continued. This will include in vivo investigation of relationships between antioxidant systems and the biochemical adaptations and injury which takes place in response to oxidant stress during development. The regulatory role of the lung glutathione (system) during hyperoxia and in protection from oxygen toxicity will be studied in detail. This will include study of the relationship of glutathione to other antioxidant systems including superoxide dismutase and Vitamin E and a detailed investigation of enzymes important for the maintenance of reduced glutathione and of the glutathione cycle. The influences of oxygen toxicity on mitrochondrial energy metabolism including glutathione status and its relationship to oxidative phosphorylation and pyruvate dehydrogenase activity and its control will also be investigated. The influence of other suspected chemical oxidants such as paraquat and BCNU and adriamycin on these systems in lungs will be studied. Differences in response to oxygen in species which are either resistant to oxygen stress or susceptible will also be measured as for example comparisons between newborn rat and hamster. In vivo and in vitro studies of the role of oxygen in inducing adaptive changes in levels of glutathione, glutathione reductase and G6PDH by measuring specific protein and mRNA synthesis in response to alterations on oxygen environment will be an important extension of current work. Explants of fetal and newborn lung and isolated type II cells from fetal and newborn rat lungs will be utilized to examine antioxidant protective mechanisms including endogenous antioxidant status and levels of protective enzymes at different development stages. Examination of the functional consequences of oxidant injury and its prevention in both in vivo and in vitro systems as they relate to glutathione and other antioxidant mechanisms will be continued. This will include studies of hyperoxic influences on surfactant phospholipid synthesis, the activity of specific mono-oxygenases in lung and specific examination of in vivo and in vitro membrane lipid peroxidation. In all of these studies we will seek morphologic correlates at the light and electron microscopic levels.