Am. J. Respir. Cell Mol. Biol., Volume 19, Number 3, September, 1998 387-399

Relationship of Inhaled Ozone Concentration to Acute Tracheobronchial Epithelial Injury, Site-specific Ozone Dose, and Glutathione Depletion in Rhesus Monkeys

Charles G. Plopper, Gary E. Hatch, Viviana Wong, Xiuchen Duan, Alison J. Weir, Brian K. Tarkington, Robert B. Devlin, Suzanne Becker, and A. R. Buckpitt

Departments of Anatomy, Physiology and Cell Biology, and Molecular Biosciences, School of Veterinary Medicine; California Regional Primate Research Center, University of California, Davis, California; and National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina

Acute pulmonary epithelial injury produced by short-term exposure to ozone varies by site within the tracheobronchial tree. To test whether this variability is related to the local dose of ozone at the tissue site or to local concentrations of glutathione, we exposed adult male rhesus monkeys for 2 h to filtered air or to 0.4 or 1.0 ppm ozone generated from ¹⁸O₂. Following exposure, lungs were split into lobes and specimens were selected by microdissection so that measurements could be made on airway tissue of similar branching history, including trachea, proximal (generation one or two) and distal (generation six or seven) intrapulmonary bronchi, and proximal respiratory bronchioles. One half of the lung was lavaged for analysis of extracellular components. In monkeys exposed to filtered air, the concentration of reduced glutathione (GSH) varied throughout the airway tree, with the proximal intrapulmonary bronchus having the lowest concentration and the parenchyma having the highest concentration. Exposure to 1.0 ppm ozone significantly reduced GSH only in the respiratory bronchiole, whereas exposure to 0.4 ppm increased GSH only in the proximal intrapulmonary bronchus. Local ozone dose (measured as excess ¹⁸O) varied by as much as a factor of three in different airways of monkeys exposed to 1.0 ppm, with respiratory bronchioles having the highest concentration and the parenchyma the lowest concentration. In monkeys exposed to 0.4 ppm, the ozone dose was 60% to 70% less than in the same site in monkeys exposed to 1.0 ppm. Epithelial disruption was present to some degree in all airway sites, but not in the parenchyma, in animals exposed to 1.0 ppm ozone. The mass of mucous and ciliated cells decreased in all airways, and necrotic and inflammatory cells increased. At 0.4 ppm, epithelial injury was minimal, except in the respiratory bronchiole, where cell loss and necrosis occurred, and was 50% that found in monkeys exposed to 1.0 ppm ozone. We conclude that there is a close association between site-specific O₃ dose, the degree of epithelial injury, and glutathione depletion at local sites in the tracheobronchial tree.

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