Our overall goal is to understand what determines whether cells in the intact lung can (do) or cannot (do not) respond to hyperoxia with an increase in antioxidant enzyme (AOE) activity; in essence we wish to understand tolerance to hyperoxia as it occurs in lung cells. Toward this goal we offer three specific aims that are increasingly reductionistic but critically interdependent. We propose: 1) To continue studies using whole rat lungs to detect the level(s) at which the expression of genes for the antioxidant enzymes Cu, Zn superoxide dismutase, Mn superoxide dismutase, catalase, and glutathione peroxidase are regulated (a) to bring about the late gestational increase in activity of these enzymes, and, (b) the increased activity in instances of endogenous or induced tolerance to hyperoxia. 2) To use in situ hybridization and immunolocalization of the AOE, in a quantitative ultrastructural analysis of the intact rat lung, to permit comparison of the AOE response of in vivo cells to hyperoxia with the AOE response to hyperoxia by specific lung cells in culture; our goal here is to evaluate the physiological relevance of the in vitro response of specific cells to hyperoxia. 3) To isolate and clone rat genes for Cu, Zn superoxide dismutase and Mn superoxide dismutase and explore their regulation. Based on our progress to date, the probes we have in hand, and our aggregate experience, we think we are in a favorable position to achieve our aims. Although we are mainly interested in the lung, we think our studies will contribute to an understanding of tolerance to oxidants, which will be of interest to biologists, physiologists, and physicians, and that will eventually be translated into the prevention of 02- toxicity in the lung and perhaps other forms of oxidant damage to other organs.
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