In pediatric and adult respiratory care units, nosocomial pneumonia is a leading cause of patient morbidity, mortality and economic loss. Clinical investigations suggest that this infectious complication is due to diminished numbers and decreased function of the resident lung phagocyte, the pulmonary alveolar macrophage (PAM). We hypothesize that these alterations in the PAM are induced by hyperoxia, and the mechanisms involved include 1) injury to antioxidant enzyme systems, 2) damage to DNA, and 3) depressed protein synthesis. We postulate that 1) cimetidine prevents oxidant injury by decreasing hydrogen peroxide production via the cytochrome P-450 oxygenase system, and 2) deferoxamine blocks hydroxyl and perferryl radical production in metal-catalyzed reactions, thereby reducing oxidant injury to the lung during normobaric, hyperoxic exposures. To test these hypotheses, the following investigations will be performed in rabbits who receive cimetidine, deferoxamine, or drug placebo during exposure to hyperoxia: 1. In vivo pulmonary clearance of inhaled Staphylococcus aureus and Escherichia coli 2. Assessment of 02-dependent and 02-independent bactericidal mechanisms by the PAM 3. Determination of cell kinetics of the PAM population 4. Measurement of antioxidant enzyme systems of the PAM 5. Assessment of DNA damage and repair in the PAM population 6. Determination of polyamine metabolism by the PAM 7. Evaluation of lung morphometrics during acute injury, convalescence, and recovery The PAM has a secretory repertoire that includes over 50 mediators of pulmonary host defense, growth, and repair. The findings derived from these investigations should enhance our understanding of pulmonary alveolar macrophage injury and repair during hyperoxia. In addition, our observations will have broad applications to the fields of cancer biology and aging.
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