We have been exploring the biochemical basis for the reported potentiation of lung bacterial infection by the air pollutant ozone. This protocol is based upon ongoing studies demonstrating that ozone inhalation results in a marked decrement in the ability of mouse pulmonary alveolar macrophages (PAM) to produce superoxide anion radical (O2.) upon activation with soluble or particulate stimuli. We observe this finding following three hours of exposure to ozone levels in the range of the current US ambient Air Quality Standard for ozone of 0.12 ppm for 1 hour. This could account for the ability of ozone to potentiate bacterial infections in mice, an effect reported to occur at concentrations as low as 0.08 ppm. As the effect on O2. production is not accompanied by any decrement in phagocytosis in our studies, the findings are analogous to those observed in the polymorphonuclear leukocytes (PMN) of humans with Chronic Granulomatous Disease (CGD). It requires far higher levels of ozone (> 1 ppm) to produce this effect in rats, a species that is relatively insensitive in the infectivity model.
The Specific Aims of the studies in the present protocol are: 1. To determine the mechanism of the decrease in PAM 02. production by studying the effect of ozone on the following parameters reflecting PAM membrane function: cytochrome b245, FAD, ubiquinone, membrane sulfhydryl oxidation, membrane lipid fluidity. 2. To extend the observation to nitrogen dioxide, which also potentiates bacterial infection in mice at relatively low pollutant concentrations, by studying: a. The effect of NO2 on O2. production by mouse PAM. b. Depending in part on these findings, the mechanistic studies as described in 1. above will be repeated using N02. 3. To develop information concerning the potential applicability of these findings, and indirectly of the infectivity model, to humans by: a. Developing an in vitro system in which exposure of PAM from various species will give results analogous to that observed in vivo for rats and mice. b. Using this in vitro system to test whether human PAM respond more like rat (insensitive to infectivity) or mouse (sensitive to infectivity in PAM)
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