Comparative Protection Against Liver Inflammation and Fibrosis by a Selective COX-2 Inhibitor and a Nonredox-type 5-LO Inhibitor

In this study, we examined the relative contribution of cyclooxygenase-2 (COX-2) and 5lipoxygenase (5-LO), two major pro-inflammatory pathways up-regulated in liver disease, to the progression of hepatic inflammation and fibrosis. Separate administration of SC-236, a selective COX-2 inhibitor, and CJ-13,610, a 5-LO inhibitor, to carbon tetrachloride (CCl4)treated mice significantly reduced fibrosis as revealed by the analysis of Sirius Red-stained liver sections without affecting necro-inflammation. Conversely, combined administration of SC-236 and CJ-13,610 reduced both necro-inflammation and fibrosis. These findings were confirmed in 5-LO-deficient mice receiving SC-236, which also showed reduced hepatic monocyte chemoattractant protein 1 (MCP-1) expression. Interestingly, SC-236 and CJ-13,610 significantly increased the number of non-parenchymal liver cells with apoptotic nuclei (TUNEL-positive). Additional pharmacological profiling of SC-236 and CJ-13,610 was performed in macrophages, the primary hepatic inflammatory cell type. In these cells, SC-236 inhibited prostaglandin (PG) E2 formation in a concentration-dependent manner, whereas CJ13,610 blocked leukotriene B4 biosynthesis. Of note, the simultaneous addition of SC-236 and CJ-13,610 resulted in a higher inhibitory profile on PGE2 biosynthesis than the dual COX/5LO inhibitor licofelone. These drugs differentially regulated interleukin-6 mRNA expression in macrophages. Taken together, these findings indicate that both COX-2 and 5-LO pathways are contributing factors to hepatic inflammation and fibrosis and that these two pathways of the arachidonic acid cascade represent potential targets for therapy. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on August 31, 2007 as DOI: 10.1124/jpet.107.128264 at A PE T Jornals on D ecem er 9, 2021 jpet.asjournals.org D ow nladed from