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

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)201-210
Number of pages10
JournalPancreatology
Volume14
Issue number3
DOIs
Publication statusPublished - Jan 1 2014

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Hepatology
  • Gastroenterology

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