Am. J. Respir. Crit. Care Med., Volume 161, Number 1, January 2000, 249-256

Nitric Oxide Synthase Inhibitors Attenuate Ozone-induced Airway Inflammation in Guinea Pigs
Possible Role of Interleukin-8

HIROMASA INOUE, HISAMICHI AIZAWA, HIROYUKI NAKANO, KOICHIRO MATSUMOTO, KAZUYOSHI KUWANO, JAY A. NADEL, and NOBUYUKI HARA

Research Institute for Diseases of the Chest, Faculty of Medicine, Kyushu University, Fukuoka, Japan; and Cardiovascular Research Institute and Department of Medicine, University of California, San Francisco, California

Nitric oxide (NO) is increased in exhaled air of asthmatics. We hypothesized that endogenous NO contributes to airway inflammation and hyperresponsiveness, and that interleukin-8 (IL-8) might be involved in this mechanism. In human transformed bronchial epithelial cells in vitro, NO donors increased IL-8 production dose-dependently. In addition, tumor necrosis factor- (TNF-) plus IL-1 plus interferon- (IFN-) increased IL-8 in culture supernatant of epithelial cells; the combination of NO synthase (NOS) inhibitors, aminoguanidine (AG) plus N^G-nitro-L-arginine methyl ester (L-NAME) attenuated the cytokine-induced IL-8 production in epithelial cells. In guinea pigs in vivo, ozone exposure induced airway hyperresponsiveness to acetylcholine and increased neutrophils in bronchoalveolar lavage fluid (BALF), and these changes persisted for at least 5 h. Pretreatment with NOS inhibitors had no effect on airway hyperresponsiveness or neutrophil accumulation immediately after ozone, but significantly inhibited the changes 5 h after ozone. NOS inhibitors also attenuated the increases of nitrite/nitrate levels in BALF and the IL-8 mRNA expression in epithelial cells and in neutrophils in guinea pig airways 5 h after ozone. These results suggest that endogenous NO may play an important role in the persistent airway inflammation and hyperresponsiveness after ozone exposure, presumably partly through the upregulation of IL-8. Inoue H, Aizawa H, Nakano H, Matsumoto K, Kuwano K, Nadel JA, Hara N. Nitric oxide synthase inhibitors attenuate ozone-induced airway inflammation in guinea pigs: possible role of interleukin-8.

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