The inhibitory effects of rebamipide on cigarette smoke-induced airway mucin production

초록

Cigarette smoke may be the main cause of chronic bronchitis. Exposure of cigarette smoke induces the recruitment of inflammatory cells in the airway epithelium, and release of the tumor necrosis factor alpha (TNF alpha) from airways. Previous reports have shown that cigarette smoke induces goblet cell metaptasia by activating an epidermal growth factor receptor (EGFR) cascade, and that this results in mucin production. Rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid, OPC-12759) directly inhibits the production of superoxide (O-2(-)) and inhibits proinflammatory cytokines (such as TNF alpha and IL-8). In the present study, we aimed to analyze the inhibitory effects of rebamipide on TNF alpha and EGFR activation after cigarette smoke treatment in vitro and in vivo. NCl-H292 cells and Sprague-Dawley rats were used for in vitro and in vivo studies. In vitro studies, cigarette smoke solution was found to increase TNFa secretion, and EGFR-specific tyrosine phosphorylation, and to elevate MUC5AC production. These effects were inhibited dose-dependently by pretreatment with rebamipide (MUC5AC protein levels were inhibited from 44% to 17%, P < 0.05). In vivo studies, cigarette smoke was found to cause inflammatory cell recruitment and to increase the secretion of TNFa in bronchoalveolar lavage (BAL) fluids (from 198 +/- 78 to 2270 +/- 158 pg/ml, P < 0.01). Moreover, the pretreatment of rats with rebamipide inhibited goblet cell metaplasia and TNF alpha secretion, dose-dependently (from 2270 +/- 158 to 1377 +/- 112 pg/ml, P < 0.05). In conclusion, the exposure of airway epithelium to cigarette smoke-induced TNF alpha production, neutrophit recruitment, activated EGFR, and caused MUC5AC mucin synthesis. Moreover, rebamipide was found to prevent this cigarette smoke-induced TNF alpha release, and mucin production. (c) 2005 Elsevier Ltd. All rights reserved.

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