1. Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis.
- Author
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Rullier A, Gillibert-Duplantier J, Costet P, Cubel G, Haurie V, Petibois C, Taras D, Dugot-Senant N, Deleris G, Bioulac-Sage P, and Rosenbaum J
- Subjects
- Animals, Carbon Tetrachloride, Cell Hypoxia, Chemokine CCL2 metabolism, Chemotaxis, Leukocyte, Collagen Type I genetics, Collagen Type I metabolism, Connective Tissue Growth Factor, Disease Models, Animal, Genotype, Immediate-Early Proteins metabolism, Intercellular Signaling Peptides and Proteins metabolism, Lipid Peroxidation, Liver enzymology, Liver pathology, Liver Cirrhosis chemically induced, Liver Cirrhosis genetics, Liver Cirrhosis metabolism, Liver Cirrhosis pathology, Male, Matrix Metalloproteinase 2 genetics, Matrix Metalloproteinase 2 metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Necrosis, RNA, Messenger metabolism, Receptor, PAR-1 deficiency, Receptor, PAR-1 genetics, Receptor, Platelet-Derived Growth Factor beta genetics, Receptor, Platelet-Derived Growth Factor beta metabolism, T-Lymphocytes metabolism, Transaminases blood, Liver metabolism, Liver Cirrhosis prevention & control, Receptor, PAR-1 metabolism, Thrombin metabolism
- 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.
- Published
- 2008
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