The inhibitory effects of rebamipide on cigarette smoke-induced airway mucin production.
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.
Lee
Sung Yong
SY
Division of Pulmonology, Department of Internal Medicine, Guro Hospital, Korea University, #80, Guro-dong, Guro-gu, Seoul 152-703, Republic of Korea.
Kang
Eun Joo
EJ
Hur
Gyu Young
GY
Jung
Ki Hwan
KH
Jung
Hye Cheol
HC
Lee
Sang Yeub
SY
Kim
Je Hyeong
JH
Shin
Chol
C
In
Kwang Ho
KH
Kang
Kyung Ho
KH
Yoo
Se Hwa
SH
Shim
Jae Jeong
JJ
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*
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