Nitric oxide synthase inhibitors attenuate ozone-induced airway inflammation in guinea pigs. Possible role of interleukin-8.
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-alpha (TNF-alpha) plus IL-1beta plus interferon-gamma (IFN-gamma) 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
H
Research Institute for Diseases of the Chest, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Aizawa
H
H
Nakano
H
H
Matsumoto
K
K
Kuwano
K
K
Nadel
J A
JA
Hara
N
N
D000109:Acetylcholine; D000818:Animals; D015152:Blotting, Northern; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001991:Bronchitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D017403:In Situ Hybridization; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010126:Ozone / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D019323:omega-N-Methylarginine / Q000494:pharmacology
D017931:DNA Primers; D004791:Enzyme Inhibitors; D006146:Guanidines; D016209:Interleukin-8; D012333:RNA, Messenger; D019323:omega-N-Methylarginine; D010126:Ozone; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester