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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Thrombin and Protease-Activated Receptor-1 Agonists Promote Lipopolysaccharide-Induced Hepatocellular Injury in Perfused Livers

Bryan L. Copple, Frederic Moulin, Umesh M. Hanumegowda, Patricia E. Ganey and Robert A. Roth
Journal of Pharmacology and Experimental Therapeutics May 2003, 305 (2) 417-425; DOI: https://doi.org/10.1124/jpet.102.046391
Bryan L. Copple
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Frederic Moulin
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Umesh M. Hanumegowda
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Patricia E. Ganey
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Robert A. Roth
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Abstract

Bacterial lipopolysaccharide (LPS) is a potent inflammatory agent capable of producing liver injury, the pathogenesis of which depends on numerous mediators, including thrombin. Previous studies showed that thrombin promotes LPS-induced liver injury independent of its ability to form fibrin clots. In isolated, buffer-perfused livers from LPS-treated rats, thrombin added to the perfusion buffer caused dose-dependent liver injury with an EC50 value of 0.4 nM, consistent with activation by thrombin of a protease-activated receptor (PAR). Actions of thrombin at PARs can be mimicked by thrombin receptor-activating peptides (TRAPs). TRAPs for PAR-1 reproduced the injury caused by thrombin in isolated livers, suggesting that one mechanism by which thrombin promotes LPS-induced liver injury is by activating PAR-1. Immunocytochemistry demonstrated the presence of PAR-1 on sinusoidal endothelial cells and Kupffer cells but not on parenchymal cells or neutrophils. Previous studies showed that thrombin interacts with neutrophils in the genesis of liver injury after LPS treatment. To explore this interaction further, the influence of thrombin on mediators that modulate neutrophil function were evaluated. Inhibition of thrombin in LPS-treated rats prevented liver injury but did not prevent up-regulation of cytokine-induced neutrophil chemoattractant-1, macrophage inflammatory protein-2, or intercellular adhesion molecule-1. Thrombin inhibition did, however, prevent neutrophil (PMN) degranulation in vivo as measured by plasma elastase levels. In addition, elastase concentration was increased in the perfusion medium of livers isolated from LPS-treated rats and perfused with TRAPs. These results suggest that activation of PAR-1 after LPS exposure promotes PMN activation and hepatic parenchymal cell injury.

Footnotes

  • This work was supported by National Institutes of Health Grant DK50728. F.M. and B.C. were supported, in part, by National Institutes of Health Training Grant T32 ES07255. B.C. was also supported by NRSA ES05866 from National Institutes of Health.

  • DOI: 10.1124/jpet.102.046391

  • Abbreviations:
    LPS
    lipopolysaccharide
    PMN
    neutrophil
    PAR
    protease-activated receptor
    TRAP
    thrombin receptor-activating peptide
    SEC
    sinusoidal endothelial cell
    ICAM-1
    intercellular adhesion molecule-1
    FBS
    fetal bovine serum
    PBS
    phosphate-buffered saline
    SFFLRN
    Ser-Phe-Phe-Leu-Arg-Asn
    TFLLR
    Thr-Phe-Leu-Leu-Arg
    NRLFFS
    Asn-Arg-Leu-Phe-Phe-Ser
    RLLFT
    Arg-Leu-Leu-Phe-Thr
    ALT
    alanine aminotransferase
    DAPI
    4′6-diamidino-2-phenylindole dihydrochloride
    CINC-1
    cytokine-induced neutrophil chemoattractant-1
    MIP-2
    macrophage inflammatory protein-2
    RT-PCR
    reverse transcription-polymerase chain reaction
    ELISA
    enzyme-linked immunosorbent assay
    ANOVA
    analysis of variance
    EU
    endotoxin unit
    • Received November 6, 2002.
    • Accepted January 21, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 2
1 May 2003
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Thrombin and Protease-Activated Receptor-1 Agonists Promote Lipopolysaccharide-Induced Hepatocellular Injury in Perfused Livers

Bryan L. Copple, Frederic Moulin, Umesh M. Hanumegowda, Patricia E. Ganey and Robert A. Roth
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 417-425; DOI: https://doi.org/10.1124/jpet.102.046391

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Thrombin and Protease-Activated Receptor-1 Agonists Promote Lipopolysaccharide-Induced Hepatocellular Injury in Perfused Livers

Bryan L. Copple, Frederic Moulin, Umesh M. Hanumegowda, Patricia E. Ganey and Robert A. Roth
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 417-425; DOI: https://doi.org/10.1124/jpet.102.046391
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