title: The inhibitory effects of rebamipide on cigarette smoke-induced airway mucin production.
abstract: 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 (TNFalpha) from airways. Previous reports have shown that cigarette smoke induces goblet cell metaplasia 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 (O2-) and inhibits proinflammatory cytokines (such as TNFalpha and IL-8). In the present study, we aimed to analyze the inhibitory effects of rebamipide on TNFalpha 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 TNFalpha 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 TNFalpha 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 TNFalpha 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 TNFalpha production, neutrophil recruitment, activated EGFR, and caused MUC5AC mucin synthesis. Moreover, rebamipide was found to prevent this cigarette smoke-induced TNFalpha release, and mucin production.
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, Guro Hospital, Korea University, #80, Guro-dong, Guro-gu, Seoul 152-703, Republic of Korea.
authors.forename: Sung Yong
authors.initials: SY
authors.lastname: Lee
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Kang
authors.forename: Gyu Young
authors.initials: GY
authors.lastname: Hur
authors.forename: Ki Hwan
authors.initials: KH
authors.lastname: Jung
authors.forename: Hye Cheol
authors.initials: HC
authors.lastname: Jung
authors.forename: Sang Yeub
authors.initials: SY
authors.lastname: Lee
authors.forename: Je Hyeong
authors.initials: JH
authors.lastname: Kim
authors.forename: Chol
authors.initials: C
authors.lastname: Shin
authors.forename: Kwang Ho
authors.initials: KH
authors.lastname: In
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Kang
authors.forename: Se Hwa
authors.initials: SH
authors.lastname: Yoo
authors.forename: Jae Jeong
authors.initials: JJ
authors.lastname: Shim
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D055271:Mucin 5AC; D009077:Mucins / Q000187:drug effects / Q000378:metabolism*; D015363:Quinolones / Q000627:therapeutic use*; D051381:Rats; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000975:Antioxidants; C524680:Muc5ac protein, rat; D055271:Mucin 5AC; D009077:Mucins; D015363:Quinolones; D014409:Tumor Necrosis Factor-alpha; D066246:ErbB Receptors; C052785:rebamipide; D000409:Alanine