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 in 5-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) 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.

• Authors: Raquel Horrillo, Anna Planagumà, Ana González-Périz, Natàlia Ferré, Esther Titos, Rosa Miquel, Marta López-Parra, Jaime L Masferrer, Vicente Arroyo, Joan Clària
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 323 Issue 3 Pg. 778-86 (Dec 2007) ISSN: 1521-0103 [Electronic] United States
• PMID: 17766677 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide
• CJ 13610
• Cyclooxygenase 2 Inhibitors
• Imidazoles
• Lipoxygenase Inhibitors
• Pyrazoles
• Sulfides
• Sulfonamides
• Carbon Tetrachloride
• Arachidonate 5-Lipoxygenase
• Cyclooxygenase 2
• Dinoprostone

Topics

• Animals
• Apoptosis (drug effects)
• Arachidonate 5-Lipoxygenase (genetics)
• Carbon Tetrachloride (toxicity)
• Cell Line
• Cell Survival (drug effects)
• Chemical and Drug Induced Liver Injury (enzymology, pathology, prevention & control)
• Cyclooxygenase 2 (genetics, metabolism)
• Cyclooxygenase 2 Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Dinoprostone (biosynthesis)
• Drug Therapy, Combination
• Gene Expression (drug effects)
• Gene Expression Profiling
• Imidazoles (administration & dosage, pharmacology, therapeutic use)
• In Situ Nick-End Labeling
• Lipoxygenase Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Liver Cirrhosis, Experimental (enzymology, pathology, prevention & control)
• Macrophages (drug effects, enzymology, metabolism)
• Male
• Mice
• Mice, Inbred Strains
• Oxidation-Reduction
• Pyrazoles (administration & dosage, pharmacology, therapeutic use)
• Reverse Transcriptase Polymerase Chain Reaction
• Sulfides (administration & dosage, pharmacology, therapeutic use)
• Sulfonamides (administration & dosage, pharmacology, therapeutic use)