Comparative Protection against Liver Inflammation and Fibrosis by a Selective Cyclooxygenase-2 Inhibitor and a Nonredox-Type 5-Lipoxygenase Inhibitor

Abstract

In this study, we examined the relative contribution of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO), two major proinflammatory pathways up-regulated in liver disease, to the progression of hepatic inflammation and fibrosis. Separate administration of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-236), a selective COX-2 inhibitor, and CJ-13,610, a 5-LO inhibitor, to carbon tetrachloride-treated mice significantly reduced fibrosis as revealed by the analysis of Sirius Red-stained liver sections without affecting necroinflammation. Conversely, combined administration of SC-236 and 4-[3-[4-(2-methylimidazol-1-yl)-phenylthio]]phenyl-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (CJ-13,610) reduced both necroinflammation and fibrosis. These findings were confirmed in5-LO-deficient mice receiving SC-236, which also showed reduced hepatic monocyte chemoattractant protein 1 expression. Interestingly, SC-236 and CJ-13,610 significantly increased the number of nonparenchymal liver cells with apoptotic nuclei (terminal deoxynucleotidyl transferase dUTP nick-end labeling-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) E 2 formation in a concentration-dependent manner, whereas CJ-13,610 blocked leukotriene B 4 biosynthesis. Of note, the simultaneous addition of SC-236 and CJ-13,610 resulted in a higher inhibitory profile on PGE 2 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.

Regulatory effects of arachidonate 5-lipoxygenase on hepatic microsomal TG transfer protein activity and VLDL-triglyceride and apoB secretion in obese mice

“…Mice consumed approximately 3-6 g food/day. This drug regimen exerts effective 5-LO inhibition in wild-type mice (16) and in ob/ob mice (see later discussion). At the end of the intervention period, mice were anesthetized with isoflurane and blood was collected by cardiac puncture.…”

“…The 5-LO inhibitor used in this study was the compound CJ-13,610, a nonredox-type 5-LO inhibitor provided by Pfizer (St. Louis, MO), with proven efficacy in vivo and in vitro (16)(17)(18). CJ-13,610 was incorporated into the diet by PMI Nutrition International (Brentwood, MO) to yield approximately 10 mg/kg body weight.…”

5-Lipoxygenase Activating Protein Signals Adipose Tissue Inflammation and Lipid Dysfunction in Experimental Obesity

“…Samples were treated with DNase (DNA-free) and retrotranscribed with the High-Capacity cDNA Archive Kit (Applied Biosystems, Foster City, CA). PCR amplification of 5-LO, FLAP, LTC4S, LTA4H, 12/15-LO, LTB 4 type 1 (BLT1) and type 2 (BLT2) receptors, and cysteinyl-LT type 1 (CysLT1) and type 2 (CysLT2) receptors was performed with specific oligonucleotides (Table I) (19,20). The specificity of primers was confirmed in the GenBank database, using the basic local alignment search tool, and by direct sequencing of the amplified PCR products in an ABI Prism 3130xl Genetic Analyzer using a Big Dye Terminator (version 3.1) Cycle Sequencing Kit (Applied Biosystems).…”

Effect of Celecoxib, a Selective Cyclooxygenase-2 Inhibitor on Carbon Tetrachloride Intoxication in Rats

“…28) The effect of celecoxib on the liver is still controversial. In chronic applications of CCl 4 to rodents, COX-2 inhibitor reduced, [29][30][31] or potentiated 32) liver fibrosis. The critical role of COX-2 and the effect of celecoxib on liver inflammation remained to be explored.…”