title: Suppression of fibrogenic gene expression and liver fibrosis using a synthetic prostacyclin agonist.
abstract: Chronic injury and inflammation in the liver are associated with the development of liver fibrosis. Expressions of transforming growth factor-β1 (TGF-β1) and hepatocyte growth factor (HGF) participate in the development and suppression, respectively, of liver fibrosis. Here, we investigated the effect of ONO-1301, a synthetic prostaglandin I2/IP receptor agonist, on liver fibrosis and on changes in the hepatic expressions of genes that regulate the progression of fibrosis in mice. Liver fibrosis was caused by the repetitive administration of CCl4 for 12 weeks, with ONO-1301 being administered during the last 4 weeks. The expressions of fibrogenic genes: TGF-β1, connective tissue growth factor, α-smooth muscle actin, type-I collagen, and type-III collagen were upregulated by chronic liver injury, which was associated with the expansion of myofibroblasts and the development of liver fibrosis. Treatment with ONO-1301 increased hepatic HGF mRNA expression, but decreased the expressions of TGF-β1, connective tissue growth factor, α-smooth muscle actin, and type-I and type-III collagen, which was associated with the suppression of myofibroblast expansion and liver fibrosis. Neutralizing antibody for HGF significantly attenuated the suppressive action of ONO-1301 on liver fibrosis and fibrogenic gene expressions. The therapeutic action of ONO-1301 on liver fibrosis may have occurred partly through HGF-mediated pathways.
authors.affiliation: Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Katsuya
authors.initials: K
authors.lastname: Sakai
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Chikako
authors.initials: C
authors.lastname: Tambo
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sakai
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D011725:Pyridines; C105488:ONO 1301; D017228:Hepatocyte Growth Factor