The selective cyclooxygenase-2 inhibitor SC-236 reduces liver fibrosis by mechanisms involving non-parenchymal cell apoptosis and PPARgamma activation.
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.
Planagumà
Anna
A
DNA Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain.
Clària
Joan
J
Miquel
Rosa
R
López-Parra
Marta
M
Titos
Esther
E
Masferrer
Jaime L
JL
Arroyo
Vicente
V
Rodés
Joan
J
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
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