title: Camostat mesilate attenuates pancreatic fibrosis via inhibition of monocytes and pancreatic stellate cells activity.
abstract: Camostat mesilate (CM), an oral protease inhibitor, has been used clinically for the treatment of chronic pancreatitis in Japan. However, the mechanism by which it operates has not been fully understood. Our aim was to evaluate the therapeutic efficacy of CM in the experimental pancreatic fibrosis model induced by dibutyltin dichloride (DBTC), and we also determined the effect of CM on isolated monocytes and panceatic stellate cells (PSCs). In vivo, chronic pancreatitis was induced in male Lewis rats by single administration of 7 mg/kg DBTC and a special diet containing 1 mg/g CM was fed to the DBTC+CM-treated group from day 7, while the DBTC-treated group rats were fed a standard diet. At days 0, 7, 14 and 28, the severity of pancreatitis and fibrosis was examined histologically and enzymologically in both groups. In vitro, monocytes were isolated from the spleen of a Lewis rat, and activated with lipopolysaccharide stimulation. Thereafter, the effect of CM on monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) production from monocytes was examined. Subsequently, cultured rat PSCs were exposed to CM and tested to see whether their proliferation, MCP-1 production and procollagen alpha1 messenger RNA expression was influenced by CM. In vivo, the oral administration of CM inhibited inflammation, cytokines expression and fibrosis in the pancreas. The in vitro study revealed that CM inhibited both MCP-1 and TNF-alpha production from monocytes, and proliferation and MCP-1 production from PSCs. However, procollagen alpha1 expression in PSCs was not influenced by CM. These results suggest that CM attenuated DBTC-induced rat pancreatic fibrosis via inhibition of monocytes and PSCs activity.
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Gibo
authors.forename: Tetsuhide
authors.initials: T
authors.lastname: Ito
authors.forename: Ken
authors.initials: K
authors.lastname: Kawabe
authors.forename: Terumasa
authors.initials: T
authors.lastname: Hisano
authors.forename: Masanobu
authors.initials: M
authors.lastname: Inoue
authors.forename: Nao
authors.initials: N
authors.lastname: Fujimori
authors.forename: Takamasa
authors.initials: T
authors.lastname: Oono
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Arita
authors.forename: Hajime
authors.initials: H
authors.lastname: Nawata
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004952:Esters; D005355:Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D016670:Gabexate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D006146:Guanidines; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009947:Organotin Compounds / Q000633:toxicity; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D004952:Esters; D006146:Guanidines; D009947:Organotin Compounds; D011347:Procollagen; D011480:Protease Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C034532:camostat; D016670:Gabexate; C020735:dibutyldichlorotin