title: 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.
authors.affiliation: INSERM U889, Université Victor Segalen Bordeaux 2, 146, Rue Léo Saignat, 33076 Bordeaux, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Rullier
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gillibert-Duplantier
authors.forename: Pierre
authors.initials: P
authors.lastname: Costet
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Cubel
authors.forename: Valérie
authors.initials: V
authors.lastname: Haurie
authors.forename: Cyril
authors.initials: C
authors.lastname: Petibois
authors.forename: Danièle
authors.initials: D
authors.lastname: Taras
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dugot-Senant
authors.forename: Gérard
authors.initials: G
authors.lastname: Deleris
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.forename: Jean
authors.initials: J
authors.lastname: Rosenbaum
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D015687:Cell Hypoxia; D018932:Chemokine CCL2 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D004195:Disease Models, Animal; D005838:Genotype; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D012333:RNA, Messenger / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*; D000637:Transaminases / Q000097:blood
chemical_list: C526318:CCN2 protein, mouse; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D024042:Collagen Type I; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D055513:Connective Tissue Growth Factor; D002251:Carbon Tetrachloride; D000637:Transaminases; D020797:Receptor, Platelet-Derived Growth Factor beta; D013917:Thrombin; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse