Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis.
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.
Rullier
Anne
A
INSERM U889, Université Victor Segalen Bordeaux 2, 146, Rue Léo Saignat, 33076 Bordeaux, France.
Gillibert-Duplantier
Jennifer
J
Costet
Pierre
P
Cubel
Gaëlle
G
Haurie
Valérie
V
Petibois
Cyril
C
Taras
Danièle
D
Dugot-Senant
Nathalie
N
Deleris
Gérard
G
Bioulac-Sage
Paulette
P
Rosenbaum
Jean
J
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
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