The role of tolerance in pulmonary defense mechanisms.
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Biomedical subjects
Publications and source records attributed to D E Gardner.
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Studies from this laboratory have shown that ozone produces changes in the number and function of cells obtained by pulmonary lavage. In similar experiments, rabbits exposed to levels of NO(2) from ambient to 60 ppm demonstrated increased numbers of polymorphonuclear leukocytes in the lung washings. This phenomenon persisted for more than 72 hr after a single 3-hr exposure. When streptococci were instilled in the lungs of NO(2)-exposed anesthetized rabbits 30 min before lavage, a pronounced inhibition of phagocytic activity was observed. With these criteria, NO(2) appeared less effective than ozone as a pulmonary irritant.
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Bronchial mucus contains large quantities of the antibacterial enzyme lysozyme. Acutely exposing mice or rabbits to ozone reduced the amount of active lysozyme obtainable by bronchopulmonary lavage. The effect was proportional to ozone concentration, as well as to duration of exposure. Enzyme activity returned to normal levels during the 12 hr following exposure. Ozone (5 muliters/liter; 5 parts per million) for 3 hr reduced lysozyme levels approximately 30%. Studies of the release of lysozyme by alveolar cells support the theory that loss of activity is due to in vivo oxidation of lysozyme.
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Previous studies have indicated that acute exposure to ambient concentrations of ozone (O3) as low as 196 micrograms/m3 (0.1 ppm) increases pentobarbital (PEN)-induced sleeping time in female mice. To elucidate potential mechanisms involved, additional studies were performed. A 3 h exposure to 9800 micrograms O3/m3 (5 ppm) did not affect brain concentrations of PEN at time of awakening, even though sleeping time was increased. Exposure for 3 h to 9800 micrograms O3/m3 (5 ppm) did not alter the pattern of brain or plasma metabolites of PEN. Pentobarbital clearance followed first-order kinetics with a one-compartment model. Mice exposed to 9800 micrograms O3/m3 (5 ppm) for 3 h had a 106% increase in the plasma half-life of pentobarbital; at 1960 micrograms O3/m3 (1 ppm) for 3 h, a 71% increase was observed. It therefore appears possible that PEN-induced sleeping time might be increased due to an decrease in hepatic metabolism of PEN.
Since ambient concentrations of ozone and nitrogen dioxide increase drug-induced sleeping time in female mice, potential mechanisms were sought by investigating the effects of these gases on hepatic microsomal mixed-function oxidases in female CD-1 mice. A 3-h exposure to 9800 microgram O3/m3 (5 ppm) or 9400 microgram NO2/m3 (5 ppm) did not change the concentration of cytochrome P-450 significantly. Aniline hydroxylase, but not aminopyrine N-demethylase or p-nitroanisole O-demethylase, activities were increased following a 3-h exposure to 9400 microgram O3/m3 (5 ppm). Aniline hydroxylase activity was also increased after a 2-d (5 h/d) exposure to 1960 microgram O3/m3 (1 ppm). None of these enzyme activities were affected by a 3-h exposure to 9400 microgram NO2/m3 (5 ppm). In these studies, O3 sometimes increased wet liver weight, and thus additional experiments were conducted. A 5-h exposure to 1960 microgram O3/m3 (1 ppm) caused a lesser decrease in body weight than the decrease observed after a similar air exposure. Liver wet weights were elevated after O3 exposure. However, there were no significant changes in liver dry weight, liver dry-to-wet-weight ratio, or ratios of liver (wet or dry) weight to body weight. From these data, it is concluded that mechanisms other than those investigated are responsible for the effect of O3 and NO2 on drug-induced sleeping time. However, the activity of one mixed-function oxidase was slightly increased by O3, indicating a hitherto unrecognized systemic effect of O3 exposure.
The biochemical effects of a 5-d continuous exposure to 0.45 ppm (882 microgram/m3) O3, were studied in the lungs of 2-mo-old male, specific-pathogen-free mice (Swiss Webster) and three strains of rats (Long-Evans, Wistar, and Sprague-Dawley). The results, expressed per lung, indicated a general increase in lung weight, DNA and protein contents, oxygen consumption, sulfhydryl metabolism, and the activities of several NADP+-reducing enzymes for all exposed animals relative to their controls. When the increases in the two species (mice versus three strains of rats) were compared, the mice showed significantly higher increases than the rats in several parameters. The responses among the three strains of rats were variable, but the differences were not significant. These observations suggest that Swiss Webster mice may offer a more sensitive animal model than rats for studying the pulmonary effects of a given low-level O3 exposure.
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