title: The selective cyclooxygenase-2 inhibitor SC-236 reduces liver fibrosis by mechanisms involving non-parenchymal cell apoptosis and PPARgamma activation.
abstract: The importance of inflammation in initiating the sequence of events that lead to liver fibrosis is increasingly recognized. In this study, we tested the effects of SC-236, a selective cyclooxygenase (COX)-2 inhibitor, in rats with carbon tetrachloride (CCl4)-induced liver fibrosis. Livers from CCl4-treated rats showed increased COX-2 expression and 15-deoxy-prostaglandin (PG)J2 (15d-PGJ2) formation, as well as decreased peroxisome proliferator-activated receptor (PPAR)gamma expression. In these animals, SC-236 reduced liver fibrosis as revealed by histological analysis and by a reduction in hepatic hydroxyproline levels, metalloproteinase-2 activity, and alpha-smooth muscle actin expression. Interestingly, SC-236 normalized 15d-PGJ2 levels and restored PPARgamma expression in the liver of CCl4-treated rats. In isolated hepatic stellate cells (HSCs)--the major player in liver fibrogenesis--and Kupffer cells--the cell type primarily responsible for increased hepatic COX-2-SC-236 exhibited remarkable pro-apoptotic and growth inhibitory properties. Of interest, SC-236 decreased HSC viability to a similar extent than the PPARgamma ligand rosiglitazone. Moreover, SC-236 significantly induced PPARgamma expression in HSCs and acted as a potent PPARgamma agonist in a luciferase-reporter trans-activation assay. These data indicate that, by mechanisms involving non-parenchymal cell apoptosis and PPARgamma activation, the selective COX-2 inhibitor SC-236 might have therapeutic potential for prevention of liver fibrosis.
authors.affiliation: DNA Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Planagumà
authors.forename: Joan
authors.initials: J
authors.lastname: Clària
authors.forename: Rosa
authors.initials: R
authors.lastname: Miquel
authors.forename: Marta
authors.initials: M
authors.lastname: López-Parra
authors.forename: Esther
authors.initials: E
authors.lastname: Titos
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Masferrer
authors.forename: Vicente
authors.initials: V
authors.lastname: Arroyo
authors.forename: Joan
authors.initials: J
authors.lastname: Rodés
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002251:Carbon Tetrachloride / Q000633:toxicity; D049109:Cell Proliferation; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D007728:Kupffer Cells / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D047495:PPAR gamma / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000032:analysis; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D000096926:Benzenesulfonamides
chemical_list: D000199:Actins; D002251:Carbon Tetrachloride; D052246:Cyclooxygenase 2 Inhibitors; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D047495:PPAR gamma; D015230:Prostaglandin D2; D011720:Pyrazoles; D012333:RNA, Messenger; D013449:Sulfonamides; C097240:15-deoxy-delta(12,14)-prostaglandin J2; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides