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Am. J. Respir. Cell Mol. Biol., Volume 26, Number 4, April, 2002 413-419

Deficiency in Inducible Nitric Oxide Synthase Protects Mice from Ozone-Induced Lung Inflammation and Tissue Injury

Ladan Fakhrzadeh, Jeffrey D. Laskin, and Debra L. Laskin

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

Inhalation of ozone causes Type I epithelial cell necrosis and Type II cell hyperplasia and proliferation. This is associated with an accumulation of activated macrophages in the lower lung, which we have demonstrated contribute to tissue injury. Nitric oxide (NO) is a highly reactive cytotoxic macrophage-derived mediator that has been implicated in lung damage. In the present studies we used knockout mice with a targeted disruption of the gene for inducible nitric oxide synthase (NOSII) to analyze the role of NO in ozone-induced lung inflammation and tissue injury. Treatment of wild-type control mice with ozone (0.8 ppm) for 3 h resulted in a time-dependent increase in protein and cells in bronchoalveolar lavage fluid, which reached a maximum 24-48 h after exposure. Alveolar macrophages isolated from animals treated with ozone were found to produce increased amounts of NO, as well as peroxynitrite. This was correlated with induction of NOSII protein and nitrotyrosine staining of lung macrophages in tissue sections and in culture. Production of superoxide anion and prostaglandin (PG)E2 by alveolar macrophages was also increased after ozone inhalation. In contrast, alveolar macrophages from NOSII knockout mice did not produce reactive nitrogen intermediates even after ozone inhalation. Moreover, production of PGE2 was at control levels. NOSII knockout mice were also protected from ozone-induced inflammation and tissue injury, as measured by bronchoalveolar lavage protein and cell number. There was also no evidence of peroxynitrite-mediated lung damage in these animals. Taken together, these data demonstrate that NO, produced via NOSII, and potentially, its reactive oxidative product peroxynitrite, play a critical role in ozone-induced release of inflammatory mediators and in tissue injury.

Abbreviations: bovine serum albumin, BSA; cyclooxygenase, COX; Dulbecco's modified Eagle's medium, DMEM; Hanks' balanced salt solution, HBSS; horseradish peroxidase, HRP; interferon-gamma , IFN-gamma ; lipopolysaccharide, LPS; nitric oxide, NO; inducible nitric oxide synthase, NOSII; prostaglandin E2 (PGE2); phosphate-buffered saline, PBS; superoxide dismutase, SOD; 12-O-tetradecanoyl-phorbol-13-acetate, TPA.




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