A sustained prostacyclin analog, ONO-1301, attenuates pancreatic fibrosis in experimental chronic pancreatitis induced by dibutyltin dichloride in rats.
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.
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
Yusuke
Y
Niina
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan. Electronic address: itopapa@intmed3.med.kyushu-u.ac.jp.
Tetsuhide
T
Ito
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
Takamasa
T
Oono
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
Taichi
T
Nakamura
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
Nao
N
Fujimori
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
Hisato
H
Igarashi
Ono Pharmaceutical Co., Ltd., Research Headquarters, Osaka, Japan.
Yoshiki
Y
Sakai
Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan.
Ryoichi
R
Takayanagi
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003692:Delayed-Action Preparations; D011464:Epoprostenol / Q000819:agonists; D005355:Fibrosis; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D008297:Male; D009947:Organotin Compounds; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
D015415:Biomarkers; D016207:Cytokines; D003692:Delayed-Action Preparations; D009947:Organotin Compounds; D011725:Pyridines; C105488:ONO 1301; D017228:Hepatocyte Growth Factor; D011464:Epoprostenol; C020735:dibutyldichlorotin
Chronic pancreatitis; Fibrosis; Monocytes; ONO-1301; PSC