Received for publication July 6, 2007.
Revised August 30, 2007.
Accepted for publication August 30, 2007.

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

Abstract

In this study, we examined the relative contribution of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (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 CJ-13,610 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/5-LO 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.

Key words: 5-lipoxygenase, cyclooxygenase-2, eicosanoids, fibrosis, inflammation, liver