A common initial treatment for hypoxemia in patients with lung failure secondary to chronic obstructive pulmonary diseases, pneumonia, or adult respiratory distress syndrome is elevated 02 therapy (hyperoxia). However, prolonged exposure to hyperoxia causes lung injury. The rat model of hyperoxic lung injury mimics several aspects of lung O2 toxicity observed clinically and is unique in that exposure to 85% O2 for 7 days confers tolerance to the otherwise lethal effects of 100% O2. Conversely, rats exposed to 60% O2 for 7 days become more susceptible to 100% O2. Our long-term goal is to elucidate the mechanisms of tolerance and susceptibility to 100% O2. Studies have demonstrated hyperoxia-induced changes in the activities of redox enzymes, predominantly in lung tissue homogenates, and have suggested that redox enzymes play a role in rat tolerance/susceptibility to 100% O2. However, the results of these in vitro studies do not necessarily predict hyperoxia-induced changes in the activities of redox enzymes in an intact functioning lung. We propose that measurements of the activities of redox enzymes in intact lungs of rats exposed to 60% O2 and 85% O2 can provide critical insights into the role of these enzymes in conferring tolerance or susceptibility to 100% O2. Thus, the specific aims are: 1) Develop an experimental protocol and a mathematical model for quantitative evaluation of the activities of redox enzymes in intact lungs. 2) Use the tools developed under specific aim 1 to determine the effects of 7-day rat exposure to 60% O2 and 85% O2 on the activities of redox enzymes in intact lungs. The general approach will be to measure the venous outflow blood concentrations of probes for targeted redox enzymes during the injection of these probes into the arterial inlet of isolated perfused lungs of rats exposed to room air, 60% O2 or 85% O2. Mathematical modeling will be used to interpret the resulting data and to determine the activities of the targeted redox enzymes in intact lungs. Statistical analysis will determine which redox enzymes are differentially altered by a 7-day exposure to 60% O2 and 85% O2. Demonstration that the activity of a redox enzyme in intact lungs is differentially altered by exposure to 60% O2 and 85% 02 would be suggestive of a role in conferring susceptibility or tolerance to 100% O2. Such results will provide targets for future mechanistic studies designed to evaluate the utility of the differentially altered redox enzymes as potential therapeutic targets for protection from O2 toxicity. ? ? ?
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