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Superoxide Dismutase–Overexpressing Mice Are Resistant to Ozone-Induced Tissue Injury and Increases in Nitric Oxide and Tumor Necrosis Factor-

Environmental and Occupational Health Science Institute, Rutgers University, and University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey

Address correspondence to: Dr. Debra Laskin, Rutgers University, Department of Pharmacology and Toxicology, 160 Frelinghuysen Road, Piscataway, NJ 08854. E-mail: laskin{at}eohsi.rutgers.edu

Reactive oxygen intermediates have been implicated in lung injury induced by inhaled irritants. The present studies used mice overexpressing Cu/Zn-superoxide dismutase (SOD+/+) to analyze their role in ozone-induced lung inflammation and cytotoxicity. Treatment of wild-type mice with ozone (0.8 ppm, 3 h) resulted in increased bronchoalveolar lavage fluid protein, which was maximal after 24–48 h. Significant increases in lung macrophages and 4-hydroxyalkenals were also observed. In contrast, bronchoalveolar lavage fluid protein and macrophage content and 4-hydroxyalkenals were at control levels in ozone-treated SOD+/+ mice. There was also no evidence of peroxynitrite-mediated lung damage, demonstrating that SOD+/+ mice are resistant to ozone toxicity. Whereas alveolar macrophages from wild-type mice produced increased amounts of nitric oxide and expressed more inducible nitric oxide synthase, phospholipase A₂, and tumor necrosis factor- after ozone inhalation, this was not evident in cells from SOD+/+ mice. Ozone-induced decreases in interleukin-10 were also not observed. In wild-type mice, ozone inhalation resulted in activation of nuclear factor-B, which regulates proinflammatory gene activity. This response was significantly reduced in SOD+/+ mice. These data demonstrate that antioxidant enzymes play a critical role in ozone-induced tissue injury and in inflammatory mediator production.

Abbreviations: bovine serum albumin, BSA • cyclooxygenase, COX • Dulbecco's modified Eagle's medium, DMEM • glutathione, GSH • Hanks' balanced salt solution, HBSS • 4-hydroxynonenal, 4-HNE • horseradish peroxidase, HRP • interferon , IFN- • interleukin-10, IL-10 • lipopolysaccharide, LPS • monochlorobimane, MCB • inducible nitric oxide synthase, NOSII • inhibitory B, IB • nuclear factor B, NF-B • prostaglandin E₂, PGE₂ • phosphate-buffered saline, PBS • superoxide dismutase, SOD • Cu/Zn-superoxide dismutase overexpressor, SOD+/+ • tumor necrosis factor-, TNF- • 12-O-tetradecanoyl-phorbol-1, TPA

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