Camostat mesilate attenuates pancreatic fibrosis via inhibition of monocytes and pancreatic stellate cells activity

Junya Gibo, Tetsuhide Ito, Ken Kawabe, Terumasa Hisano, Masanobu Inoue, Nao Fujimori, Takamasa Oono, Yoshiyuki Arita, Hajime Nawata

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52 Citations (Scopus)

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-α (TNF-α) 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 α1 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-α production from monocytes, and proliferation and MCP-1 production from PSCs. However, procollagen α1 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.

Original languageEnglish
Pages (from-to)75-89
Number of pages15
JournalLaboratory Investigation
Volume85
Issue number1
DOIs
Publication statusPublished - Jan 2005

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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