The major objective of this research proposal is to establish the involvement of diffusible, cytotoxic products of peroxidation in hyperopia-induced lung injury. The diffusible cytotoxins to be examined in mammalian systems in vitro and in vivo include toxic lipid aldehydes (4-hydroxyalkenals such as 4-2hydroxynonenal), toxic lipid hydroperoxides, and H202. These substances were selected for study on the basis of 1) direct evidence in the literature that peroxidation is accompanied by the formation of these toxins, and 2) known toxic effects of these diffusible cytotoxins are very similar to the observed in vivo toxicities with hyperoxic exposure. The initial focus of this research will be to characterize the contribution of these cytotoxic substances to the lung injury process initiated by hyperopia utilizing in vivo (newborn rabbit) as well as in vitro systems (selected lung cells in culture and H202-resistant cells). The degree of oxygen-induced injury (or protection from injury) in the lung as well as in cell culture systems will be assayed by quantitative assessment of selected morphologic, biochemical, physiological, and survival parameters. Differential lung cell sensitivity to O2-induced injury will be correlated with the production of and/or susceptibility to diffusible cytotoxins. The effects of clinically significant nutritional modifications, pharmacologic agents, and antioxidant enzymes on the production of and the susceptibility of different cell types to these cytotoxins will also be investigated. The goal of this research is to identify therapeutic protocols that will provide protection from hyperoxia-induced lung damage in prematurely born infants.
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