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

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-1301-treated 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-1301-treated 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-1β, 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.

• Authors: Yusuke Niina, Tetsuhide Ito, Takamasa Oono, Taichi Nakamura, Nao Fujimori, Hisato Igarashi, Yoshiki Sakai, Ryoichi Takayanagi
• Journal: Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] (Pancreatology) 2014 May-Jun Vol. 14 Issue 3 Pg. 201-10 ISSN: 1424-3911 [Electronic] Switzerland
• PMID: 24854616 (Publication Type: Evaluation Study, Journal Article)
• Copyright: Copyright © 2014 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Chemical References

• Biomarkers
• Cytokines
• Delayed-Action Preparations
• Organotin Compounds
• Pyridines
• ONO 1301
• Hepatocyte Growth Factor
• Epoprostenol
• dibutyldichlorotin

Topics

• Animals
• Biomarkers (metabolism)
• Cytokines (metabolism)
• Delayed-Action Preparations
• Epoprostenol (agonists)
• Fibrosis
• Hepatocyte Growth Factor (metabolism)
• Male
• Organotin Compounds
• Pancreas (drug effects, metabolism, pathology)
• Pancreatitis, Chronic (chemically induced, drug therapy, pathology)
• Pyridines (pharmacology, therapeutic use)
• Random Allocation
• Rats
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Treatment Outcome