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LIVER AND BILIARY TRACT

Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis

¹Institut National de la Santé et de la Recherche Médicale (INSERM), U889, Bordeaux; ²IFR 66, Université Victor Segalen Bordeaux 2; ³Centre Hospitalier Universitaire (CHU) de Bordeaux, Hôpital Pellegrin, Department of Pathology; ⁴Université Victor Segalen Bordeaux 2, Animalerie spécialisée; ⁵Centre National de la Recherche Scientifique (CNRS), UMR5084 and Université Victor Segalen Bordeaux 2, Bordeaux, France

Submitted 28 September 2007 ; accepted in final form 22 October 2007

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 (CCl₄) 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 CCl₄ or its solvent for 6 wk (300 µl/kg, 3 times a week). Fibrosis area was increased 10-fold by CCl₄ 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-β 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.

hemostasis; thrombin; hypoxia; lymphocytes