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Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis.

Abstract : Thrombin inhibition protects against liver fibrosis. However, it is not known whether the thrombin profibrogenic effect is due to effects on blood coagulation or to signaling via protease-activated receptors (PARs). We took advantage of the lack of blood coagulation defects in PAR-1-knockout mice. Acute carbon tetrachloride (CCl(4)) toxicity was similar in wild-type (WT), PAR-1(-/-), and PAR-1(+/-) mice as judged by aminotransferase levels, area of liver necrosis, and liver peroxidation measured by Fourier-transformed infrared spectroscopy. Fifteen mice/group received CCl(4) or its solvent for 6 wk (300 microl/kg, 3 times a week). Fibrosis area was increased 10-fold by CCl(4) treatment in WT mice. PAR-1 deficiency protected against fibrosis, with 36% and 56% decrease in PAR-1(+/-) and PAR-1(-/-) mice, respectively (P < 0.001). Similar results were obtained for area of activated fibrogenic cells (64% and 79% decrease in PAR-1(+/-) and PAR-1(-/-) mice, respectively, P < 0.001). These findings were corroborated by measurements of type I collagen, matrix metalloproteinase-2, and PDGF-beta receptor mRNA levels. There was also a significant decrease in T lymphocyte infiltration in PAR-1-deficient mice. Altogether, these results suggest that thrombin profibrogenic effects are independent of effects on blood coagulation and are instead due to direct effects on fibrogenic cells and possibly on T lymphocytes.
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Submitted on : Thursday, September 10, 2009 - 4:31:55 PM
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Anne Rullier, Jennifer Gillibert-Duplantier, Pierre Costet, Gaëlle Cubel, Valérie Haurie, et al.. Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis.. AJP - Gastrointestinal and Liver Physiology, American Physiological Society, 2008, 294 (1), pp.G226-35. ⟨10.1152/ajpgi.00444.2007⟩. ⟨inserm-00181396⟩



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