Acute lung epithelial injuries result in a rapid infiltration of polymorphonuclear granulocytes (PMNs) into the lung which because of their ability to release reactive O2 intermediates and proteinases into their local environment, have been implicated in the pathogenesis of several different lung disorders that include adult respiratory distress syndrome. The major objective of this study is to determine how oxygen treatment might adversely affects acutely-damaged lungs undergoing a PMN inflammatory response. The specific hypotheses to be tested are that PMNs infiltrating into an acutely-damaged lung render it more sensitive to the damaging effects of O2 exposure leading to an accelerated onset of pulmonary oxygen toxicity; and that treatment with the phenyl-urea compound EDU will ameliorate the adverse effects of subsequent oxygen exposure. These hypotheses will be tested by the following specific aims: l) A previously developed model of acute lung epithelial injury based on short-term exposure to ozone (>1ppm) will be used to determine how subsequent exposure to O2 alters the inflammatory process and contributes to enhanced lung injury. 2) Normal, neutropenic and EDU-pretreated rats will be used to establish whether the presence of PMNs within an injured lung contribute to the further damage associated with subsequent exposure to elevated concentrations of O2. 3) The effects of O2 exposure on lung inflammatory cell apoptosis (programmed cell death) will be examined as a possible mechanism by which increased release of PMN-derived proteinases might account for O2-induced damage of injured lungs. 4) The potential of EDU and related compounds to act as reactive oxygen intermediate scavengers will be assessed in acutely-injured lungs, by determining whether or not in vivo treatments ameliorate O2-induced damage to lung macromolecules. 5) The consequences of O2 exposure and/or PMN-derived reactive oxygen intermediate and proteinases on lung homeostatic and repair processes will be assessed as a method for determining the mechanisms and effectiveness of EDU-treatments. Since the management of acute lung injuries often requires the use of O2 therapy to maintain blood oxygenation, the results and model systems generated by this project are prerequisite to the future development of improved strategies for the safe clinical use of oxygen. Such development requires a detailed understanding of how PMNs and O2 adversely affect the ability of the lung to maintain homeostasis and to repair the initial damage without the development of any long term adverse pathological lesions.
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