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

  1. Raquel Horrillo,
  2. Anna Planagumà,
  3. Ana González-Périz,
  4. Natàlia Ferré,
  5. Esther Titos,
  6. Rosa Miquel,
  7. Marta López-Parra,
  8. Jaime L. Masferrer,
  9. Vicente Arroyo and
  10. Joan Clària
  1. Department of Biochemistry and Molecular Genetics (R.H., A.P., A.G.-P., N.F., E.T., M.L.-P., J.C.), Pathology Laboratory (R.M.) and Liver Unit (V.A.), Hospital Clínic, Centro de Investigación Biomédica Esther Koplowitz and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Universitat de Barcelona, Barcelona, Spain; and Pfizer Global Research & Development, St. Louis Missouri (J.L.M.)
  1. Address correspondence to:
    Dr. Joan Clària, Department of Biochemistry and Molecular Genetics, Hospital Clínic, Villarroel 170, Barcelona 08036, Spain. E-mail: jclaria{at}clinic.ub.es

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.

Footnotes

  • This work was supported in part by grants from the Ministerio de Educación y Ciencia (MEC) (SAF 06/03191) and Instituto de Salud Carlos III (ISCIII) (Ciberehd). R.H. is supported by Generalitat de Catalunya-European Social Funds (2006FI-00091). A.G.-P. is supported by MEC. N.F. and M.L.-P. are under Juan de la Cierva (MEC) and ISCIII contracts, respectively.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.128264.

  • ABBREVIATIONS: COX, cyclooxygenase; PG, prostaglandin; 5-LO, 5-lipoxygenase; LT, leukotriene; CCl4, carbon tetrachloride; FLAP, 5-lipoxygenase-activating protein; SC-236, 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide; CJ-13,610, 4-[3-[4-(2-methylimidazol-1-yl)phenylthio]]phenyl-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide; MTT, 3-[4,5-dimethylthiazoyl-2-yl]-2,5-diphenyltetrazolium bromide; DMSO, dimethyl sulfoxide; LPS, lipopolysaccharide; PMA, phorbol 12-myristate 13-acetate; AA-861, (2-(12-hydroxydodeca-5,10-dinyl)-3,5,6-trimethyl-1,4-benzoquinone); MK-571, 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid; EIA, enzyme immunoassay; IL, interleukin; MCP-1, monocyte chemoattractant protein 1; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; CP-105,696, 1-[3-(4-phenyl-benzyl)-4-hydroxy-chroman-7-yl] cyclopentane carboxylic acid; RT, reverse transcription; PCR, polymerase chain reaction; LTC4S, leukotriene C4 synthase; LTA4H, leukotriene A4 hydrolase.

    • Received July 6, 2007.
    • Accepted August 30, 2007.
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  1. Published online before print August 31, 2007, doi: 10.1124/jpet.107.128264 JPET December 2007 vol. 323 no. 3 778-786
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