Thrombin stimulates fibroblast procollagen production via proteolytic activation of protease-activated receptor 1
Thrombin stimulates fibroblast procollagen production via proteolytic activation of protease-activated receptor 1
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DOI：
10.1042/bj3330121
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发表时间：
1998-07-01
影响因子：
4.1
通讯作者：
Laurent, GJ
中科院分区：
文献类型：
--
作者：
Chambers, RC;Dabbagh, K;Laurent, GJ
凝血酶是一种多功能丝氨酸蛋白酶，在血液凝固中起关键作用。它也是一种强效的间充质细胞有丝分裂原和趋化因子，因此可能在组织损伤部位间充质细胞的募集和局部增殖中起重要作用。我们假设凝血酶也可能通过直接刺激成纤维细胞前胶原的产生来影响这些部位结缔组织蛋白的沉积。为了验证这一假设，我们在48小时内评估了凝血酶对人胎儿肺成纤维细胞前胶原产生和基因表达的影响。凝血酶在1 nM及以上浓度时刺激前胶原产生，在10 nM凝血酶时最大增加幅度在60%到117%之间。凝血酶的这些作用至少部分是由于α(1)(I)前胶原mRNA的稳态水平升高所致。此外，用蛋白酶激活受体1（PAR - 1）的凝血酶受体激活肽也能重现这些作用，并且当用特异性抑制剂D - 苯丙氨酸 - 脯氨酸 - 精氨酸氯甲烷和水蛭素使凝血酶失去蛋白水解活性时，这些作用完全消失，这表明凝血酶是通过PAR - 1的蛋白水解激活来介导这些作用的。这些结果表明，凝血酶可能通过刺激成纤维细胞前胶原的产生，在正常伤口愈合和组织纤维化的发展过程中影响结缔组织蛋白的沉积。
Thrombin is a multifunctional serine protease that has a crucial role in blood coagulation. It is also a potent mesenchymal cell mitogen and chemoattractant and might therefore have an important role in the recruitment and local proliferation of mesenchymal cells at sites of tissue injury. We hypothesized that thrombin might also affect the deposition of connective tissue proteins at these sites by directly stimulating fibroblast procollagen production. To address this hypothesis, the effect of thrombin on procollagen production and gene expression by human foetal lung fibroblasts was assessed over 48 h. Thrombin stimulated procollagen production at concentrations of 1nM and above, with maximal increases of between 60 and 117 % at 10 nM thrombin. These effects of thrombin were, at least in part, due to increased steady-state levels of alpha(1)(I) procollagen mRNA, They could furthermore be reproduced with thrombin receptor-activating peptides for the protease-activated receptor 1 (PAR-1) and were completely abolished when thrombin was rendered proteolytically inactive with the specific inhibitors DPhe-Pro-ArgCH(2)Cl and hirudin, indicating that thrombin is mediating these effects via the proteolytic activation of PAR-1. These results suggest that thrombin might influence the deposition of connective tissue proteins during normal wound healing and the development of tissue fibrosis by stimulating fibroblast procollagen production.