Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis
| Autor: | Anne Rullier, Nathalie Dugot-Senant, Jean Rosenbaum, Jennifer Gillibert-Duplantier, Gérard Déléris, Cyril Petibois, Pierre Costet, Gaelle Cubel, Valérie Haurie, Paulette Bioulac-Sage, Danièle Taras |
|---|---|
| Přispěvatelé: | Fibrose hépatique et cancer du foie, Université Bordeaux Segalen - Bordeaux 2-IFR66-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Animalerie spécialisée, Université Bordeaux Segalen - Bordeaux 2, Chimie Nucléaire Analytique et Bio-environnementale (CNAB), Université Sciences et Technologies - Bordeaux 1 (UB)-Centre National de la Recherche Scientifique (CNRS), Rosenbaum, Jean |
| Rok vydání: | 2008 |
| Předmět: |
Liver Cirrhosis
Male Physiology T-Lymphocytes MESH: Cell Hypoxia MESH: Chemotaxis Leukocyte MESH: Collagen Type I MESH: Mice Knockout MESH: Lipid Peroxidation MESH: Thrombin MESH: Genotype Mice MESH: Animals Receptor Carbon Tetrachloride Chemokine CCL2 Mice Knockout Thrombin Gastroenterology Cell Hypoxia Cell biology MESH: Receptor PAR-1 Chemotaxis Leukocyte Liver Coagulation Intercellular Signaling Peptides and Proteins Matrix Metalloproteinase 2 MESH: Liver Cirrhosis medicine.drug medicine.medical_specialty Genotype [SDV.BC]Life Sciences [q-bio]/Cellular Biology Biology Collagen Type I Immediate early protein Immediate-Early Proteins Receptor Platelet-Derived Growth Factor beta Necrosis MESH: Mice Inbred C57BL MESH: Transaminases Physiology (medical) Internal medicine medicine Animals Receptor PAR-1 RNA Messenger MESH: Intercellular Signaling Peptides and Proteins MESH: Mice MESH: Chemokine CCL2 [SDV.BC] Life Sciences [q-bio]/Cellular Biology Transaminases MESH: RNA Messenger MESH: Necrosis Hepatology MESH: Carbon Tetrachloride Connective Tissue Growth Factor MESH: Immediate-Early Proteins Chemotaxis MESH: Male Mice Inbred C57BL MESH: Matrix Metalloproteinase 2 Disease Models Animal MESH: T-Lymphocytes Endocrinology Protease-Activated Receptor 1 Hemostasis Lipid Peroxidation MESH: Disease Models Animal MESH: Receptor Platelet-Derived Growth Factor beta Hepatic fibrosis MESH: Liver |
| Zdroj: | AJP-Gastrointestinal and Liver Physiology AJP-Gastrointestinal and Liver Physiology, 2008, 294 (1), pp.G226-35. ⟨10.1152/ajpgi.00444.2007⟩ |
| ISSN: | 1522-1547 0193-1857 |
| Popis: | 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 CCl4or its solvent for 6 wk (300 μl/kg, 3 times a week). Fibrosis area was increased 10-fold by CCl4treatment 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. |
| Databáze: | OpenAIRE |
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