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The Selective cyclooxygenase-2 Inhibitor SC-236 Reduces Liver Fibrosis by Mechanisms Involving Non-Parenchymal Cell Apoptosis and PPARgamma Activation

The Selective cyclooxygenase-2 Inhibitor SC-236 Reduces Liver Fibrosis by Mechanisms Involving Non-Parenchymal Cell Apoptosis and PPARgamma Activation

Anna Planagumà, Joan Clària, Rosa Miquel, Marta López-Parra, Esther Titos, Jaime L Masferrer, Vicente Arroyo, Joan Rodés

FASEB J. 2005 Jul;19(9):1120-2.

PMID: 15876570

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP170569865	SC-236		170569-86-5	Price

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