A sustained prostacyclin analog, ONO-1301, attenuates pancreatic fibrosis in experimental chronic pancreatitis induced by dibutyltin dichloride in rats

Yusuke Niina, Tetsuhide Ito, Takamasa Oono, Taichi Nakamura, Nao Fujimori, Hisato Igarashi, Yoshiki Sakai, Ryoichi Takayanagi

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Background: ONO-1301, a novel sustained-release prostacyclin agonist, has an anti-fibrotic effect on the lungs, heart, and kidneys that is partly associated with the induction of hepatocyte growth factor (HGF). This study examined the anti-fibrotic effect of ONO-1301 on chronic pancreatitis (CP) progression. Methods: CP was induced in rats in vivo by dibutyltin dichloride (DBTC). Seven days after DBTC injection (day 7), a slow-release form of ONO-1301 (10 mg/kg; ONO-1301etreated group) or vehicle (DBTC-treated group) was injected. On days 14 and 28, we evaluated the histopathological CP score and mRNA expressions of HGF, cytokines, and collagen in the pancreas by real-time RT-PCR. In vitro, monocytes and pancreatic stellate cells (PSCs) were isolated from normal rat spleen and pancreas, respectively. The cytokine and collagen expressions of monocytes and PSCs were detected by real-time RT-PCR, and PSCs proliferation was examined by BrdU assay. Results: Histopathological CP scores in vivo improved in the ONO-1301etreated group compared to the DBTC-treated group, particularly inflammatory cell infiltration on day 14 and interstitial fibrosis on day 28. HGF mRNA increased significantly after ONO-1301 administration, whereas IL-1b, TNF-α, TGF-β, MCP-1, and collagen mRNA decreased significantly. Cytokine expression in monocytes was suppressed in vitro not only by HGF, but also ONO-1301 alone. However, neither ONO-1301 nor HGF affected the proliferation, or cytokine or collagen expression of PSCs. Conclusions: ONO-1301 suppresses pancreatic fibrosis in the DBTC-induced CP model by inhibiting monocyte activity not only with induction of HGF but also by ONO-1301 itself.

元の言語英語
ページ(範囲)201-210
ページ数10
ジャーナルPancreatology
14
発行部数3
DOI
出版物ステータス出版済み - 1 1 2014

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Hepatology
  • Gastroenterology

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