Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis
Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis
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DOI：
10.1152/ajpgi.00444.2007
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发表时间：
2008-01-01
影响因子：
4.5
通讯作者：
Rosenbaum, Jean
中科院分区：
文献类型：
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作者：
Rullier, Anne;Gillibert-Duplantier, Jennifer;Rosenbaum, Jean
凝血酶抑制可防止肝纤维化。然而，目前尚不清楚凝血酶促纤维化作用是由于对血液凝固的影响还是通过蛋白酶激活受体（PAR）进行信号传导。我们利用PAR-1基因敲除小鼠缺乏凝血缺陷的优势。根据转氨酶水平、肝坏死面积和通过傅立叶变换红外光谱测量的肝过氧化反应判断，野生型（WT）、PAR-1（-/-）和PAR-1（+/-）小鼠的急性四氯化碳（CCl 4）毒性相似。15只小鼠/组接受CCl 4或其溶剂6周（300 μ l/kg，每周3次）。在WT小鼠中，CCl 4处理使纤维化面积增加10倍。PAR-1缺乏可防止纤维化，PAR-1（+/-）和PAR-1（-/-）小鼠分别减少36%和56%（P < 0.001）。对于活化的纤维化细胞的面积获得了类似的结果（PAR-1（+/-）和PAR-1（-/-）小鼠中分别减少64%和79%，P < 0.001）。I型胶原、基质金属蛋白酶-2和PDGF-β受体mRNA水平的测量结果证实了这些发现。PAR-1缺陷小鼠的T淋巴细胞浸润也显著减少。总之，这些结果表明，凝血酶促纤维化作用是独立的血液凝固的影响，而是由于对纤维化细胞和可能对T淋巴细胞的直接影响。
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 wildtype (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 mu l/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-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.