Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury
Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury
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DOI：
10.1172/jci33288
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发表时间：
2009-09-01
影响因子：
15.9
通讯作者：
Chambers, Rachel C.
中科院分区：
文献类型：
--
作者：
Scotton, Chris J.;Krupiczojc, Malvina A.;Chambers, Rachel C.
凝血级联的不受控制的激活会导致多种疾病的病理生理学，包括急性和慢性肺部疾病。凝血酶原被认为主要来自循环并响应组织损伤和微血管渗漏而局部激活。在此，我们报告人类和小鼠纤维化肺组织中凝血因子 X (FX) 的表达局部增加，并伴有与支气管和肺泡上皮相关的显着免疫染色。 FXa 是培养的原代人成人肺成纤维细胞中肌成纤维细胞分化程序的有效诱导剂，通过蛋白酶激活受体 1 (PAR1) 和整合素 α(v)beta(5) PAR1 介导的 TGF-β 激活。 α(v)β(5) 和 α-SMA 共定位于特发性肺纤维化个体肺活检标本中的纤维化病灶。此外，我们通过直接 FXa 抑制剂减轻博莱霉素诱导的小鼠肺纤维化，证明了 FXa 与纤维化发展之间的因果关系。这些数据支持我们认为的一种新的发病机制，FXa（凝血级联的中心蛋白酶）通过该机制局部表达并驱动对肺损伤的纤维化反应。这些发现预示着我们对过度促凝血活性起源的理解发生了转变，并将 PAR1 置于局部促凝血信号传导和组织重塑之间相互作用的中心。
Uncontrolled activation of the coagulation cascade contributes to the pathophysiology of several conditions, including acute and chronic lung diseases. Coagulation zymogens are considered to be largely derived from the circulation and locally activated in response to tissue injury and microvascular leak. Here we report that expression of coagulation factor X (FX) is locally increased in human and murine fibrotic lung tissue, with marked immunostaining associated with bronchial and alveolar epithelia. FXa was a potent inducer of the myofibroblast differentiation program in cultured primary human adult lung fibroblasts via TGF-beta activation that was mediated by proteinase-activated receptor-1 (PAR1) and integrin alpha(v)beta(5) PAR1. alpha(v)beta(5), and alpha-SMA colocalized to fibrotic foci in lung biopsy specimens from individuals with idiopathic pulmonary fibrosis. Moreover, we demonstrated a causal link between FXa and fibrosis development by showing that a direct FXa inhibitor attenuated bleomycin-induced pulmonary fibrosis in mice. These data support what we believe to be a novel pathogenetic mechanism by which FXa, a central proteinase of the coagulation cascade, is locally expressed and drives the fibrotic response to lung injury. These findings herald a shift in our understanding of the origins of excessive procoagulant activity and place PAR1 central to the cross-talk between local procoagulant signaling and tissue remodeling.