KJ Pendino, CR Gardner, RL Shuler, JD Laskin, SK Durham, DS Barton, S Tsuyoshi Ohnishi, T Ohnishi and DL Laskin
Dept. of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08855-0789, USA.

Inhalation of the pulmonary irritant ozone is associated with an accumulation of macrophages in the lung. These cells, along with type II epithelial cells, are activated to release increased quantities of hydrogen peroxide and nitric oxide, two reactive mediators that have been implicated in tissue injury. In the present studies we determined whether pretreatment of rats with bacterially derived endotoxin, which modulates oxidant levels in tissues, could abrogate the effects of ozone on lung injury and nitric oxide production. Acute exposure of rats to ozone (2 parts per million, 3 h) resulted in nitric oxide production in the lung as measured by electron paramagnetic resonance spin trapping. This was correlated with expression of inducible nitric oxide synthase (iNOS) mRNA in the lung as determined by in situ hybridization. Particularly high levels of iNOS were evident in alveolar macrophages and type II cells. Alveolar macrophages isolated from ozone-treated rats also expressed increased iNOS mRNA and protein as measured by Northern and Western blotting, respectively, and produced more nitric oxide compared with cells from air-exposed animals. Treatment of rats with endotoxin (5 mg/kg, intravenously), 30 min prior to ozone, was found to abrogate ozone-induced increases in iNOS mRNA and protein expression, as well as nitric oxide production by alveolar macrophages. This was associated with a reduction in ozone- induced tissue injury as determined by levels of lung lavage fluid protein. Ozone inhalation also resulted in a reduction in intracellular glutathione in alveolar macrophages, an effect that was blocked by endotoxin administration. Taken together, these data provide evidence that the protective effects of endotoxin against ozone-induced injury are mediated, at least in part, by alterations in levels of lung oxidants and antioxidants.

This article has been cited by other articles:

				L. Fakhrzadeh, J. D. Laskin, C. R. Gardner, and D. L. Laskin Superoxide Dismutase-Overexpressing Mice Are Resistant to Ozone-Induced Tissue Injury and Increases in Nitric Oxide and Tumor Necrosis Factor-{alpha} Am. J. Respir. Cell Mol. Biol., March 1, 2004; 30(3): 280 - 287. [Abstract] [Full Text] [PDF]

				L. Fakhrzadeh, J. D. Laskin, and D. L. Laskin Deficiency in Inducible Nitric Oxide Synthase Protects Mice from Ozone-Induced Lung Inflammation and Tissue Injury Am. J. Respir. Cell Mol. Biol., April 1, 2002; 26(4): 413 - 419. [Abstract] [Full Text] [PDF]

				S. R. Kleeberger, S. P. M. Reddy, L.-Y. Zhang, H.-Y. Cho, and A. E. Jedlicka Toll-like receptor 4 mediates ozone-induced murine lung hyperpermeability via inducible nitric oxide synthase Am J Physiol Lung Cell Mol Physiol, February 1, 2001; 280(2): L326 - L333. [Abstract] [Full Text] [PDF]

				H. INOUE, H. AIZAWA, H. NAKANO, K. MATSUMOTO, K. KUWANO, J. A. NADEL, and N. HARA Nitric Oxide Synthase Inhibitors Attenuate Ozone-induced Airway Inflammation in Guinea Pigs . Possible Role of Interleukin-8 Am. J. Respir. Crit. Care Med., January 1, 2000; 161(1): 249 - 256. [Abstract] [Full Text]

				J. A Nightingale, D. F Rogers, and P. J Barnes Effect of inhaled ozone on exhaled nitric oxide, pulmonary function, and induced sputum in normal and asthmatic subjects Thorax, December 1, 1999; 54(12): 1061 - 1069. [Abstract] [Full Text]

				D C Chambers, W S Tunnicliffe, and J G Ayres Acute inhalation of cigarette smoke increases lower respiratory tract nitric oxide concentrations Thorax, August 1, 1998; 53(8): 677 - 679. [Abstract] [Full Text]