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)

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES002510-08
Application #
3249833
Study Section
Toxicology Study Section (TOX)
Project Start
1980-05-01
Project End
1991-06-30
Budget Start
1989-07-01
Budget End
1991-06-30
Support Year
8
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Witz, G; Latriano, L; Goldstein, B D (1989) Metabolism and toxicity of trans,trans-muconaldehyde, an open-ring microsomal metabolite of benzene. Environ Health Perspect 82:19-22
Witz, G (1989) Biological interactions of alpha,beta-unsaturated aldehydes. Free Radic Biol Med 7:333-49
Ryer-Powder, J E; Amoruso, M A; Czerniecki, B et al. (1988) Inhalation of ozone produces a decrease in superoxide anion radical production in mouse alveolar macrophages. Am Rev Respir Dis 138:1129-33
Witz, G; Lawrie, N J; Goldstein, B D et al. (1988) Effects of alpha, beta-unsaturated aldehydes on macrophage and neutrophil membrane function, fluidity and sulfhydryl status. Basic Life Sci 49:849-51
Witz, G; Lawrie, N J; Amoruso, M A et al. (1987) Inhibition by reactive aldehydes of superoxide anion radical production from stimulated polymorphonuclear leukocytes and pulmonary alveolar macrophages. Effects on cellular sulfhydryl groups and NADPH oxidase activity. Biochem Pharmacol 36:721-6
Cooper, K O; Witz, G; Witmer, C M (1987) Mutagenicity and toxicity studies of several alpha,beta-unsaturated aldehydes in the Salmonella typhimurium mutagenicity assay. Environ Mutagen 9:289-95
Cooper, K O; Witmer, C M; Witz, G (1987) Inhibition of microsomal cytochrome c reductase activity by a series of alpha, beta-unsaturated aldehydes. Biochem Pharmacol 36:627-31
Witz, G; Lawrie, N J; Zaccaria, A et al. (1986) The reaction of 2-thiobarbituric acid with biologically active alpha,beta-unsaturated aldehydes. J Free Radic Biol Med 2:33-9
Borek, C; Zaider, M; Ong, A et al. (1986) Ozone acts alone and synergistically with ionizing radiation to induce in vitro neoplastic transformation. Carcinogenesis 7:1611-3
Amoruso, M A; Ryer, J; Easton, D et al. (1986) Estimation of risk of glucose 6-phosphate dehydrogenase-deficient red cells to ozone and nitrogen dioxide. J Occup Med 28:473-9

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