Protease-Activated Receptor-2 Induces Myofibroblast Differentiation and Tissue Factor Up-Regulation during Bleomycin-Induced Lung Injury Potential Role in Pulmonary Fibrosis
Protease-Activated Receptor-2 Induces Myofibroblast Differentiation and Tissue Factor Up-Regulation during Bleomycin-Induced Lung Injury Potential Role in Pulmonary Fibrosis
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DOI：
10.2353/ajpath.2010.091107
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发表时间：
2010-12-01
影响因子：
6
通讯作者：
Spek, C. Arnold
中科院分区：
文献类型：
--
作者：
Borensztajn, Keren;Bresser, Paul;Spek, C. Arnold
特发性肺纤维化是纤维化性肺疾病中最具破坏性的形式，目前的治疗方法仍然难以治愈。在肺纤维化期间，凝血非级联蛋白经常被激活，但迄今为止，这一观察结果尚未得到机制上的解释。最近的数据表明，蛋白酶激活受体（PAR） 2a被凝血因子(F)Xa激活，在纤维化疾病中起着关键作用，因此我们评估了PAR 2a在纤维化疾病中的作用我们发现，特发性肺纤维化患者的肺中PAR 2被上调，这些患者的支气管肺泡洗出液显示出增加的促凝活性，从而触发成纤维细胞的存活。通过肺纤维化模型，我们发现，在PAR 2-/-小鼠中，博来霉素诱导PAR 2的表达以及肌成纤维细胞分化和胶原合成，同时影响了纤维化的程度和严重程度病变减少，而肌成纤维细胞分化减少，胶原表达减少。此外，与野生型小鼠相比，纤维化PAR 2-/-小鼠的肺纤维蛋白沉积减少，这是由于对博来霉素的不同组织因子表达所致。综上所述，这些结果表明PAR 2在肺纤维化的发展中起重要作用，抑制PAR 2凝血轴可能为治疗这种毁灭性疾病提供一种新的治疗方法（美国病理学杂志2010年177 2753-2764 DOI 10 2353/ajpath 2010 091107）。
Idiopathic pulmonary fibrosis constitutes the most devastating form of fibrotic lung disorders and re mains refractory to current therapies The coagula non cascade is frequently activated during pulmonary fibrosis but this observation has so far resisted a mechanistic explanation Recent data suggest that protease activated receptor (PAR) 2 a receptor activated by (among others) coagulation factor (F)Xa plays a key role in fibrotic disease consequently we assessed the role of PAR 2 m the development of pulmonary fibrosis in this study We show that PAR 2 is up regulated in the lungs of patients with idiopathic pulmonary fibrosis and that bronchoalveolar lavage fluid from these patients displays increased procoagulant activity that triggers fibroblast survival Using a bleomycin model of pulmonary fibrosis we show that bleomycin induces PAR 2 expression as well as both myofibroblast differentiation and collagen synthesis In PAR 2-/- mice both the extent and severity of fibrotic lesions are reduced whereas myofibroblast differentiation is diminished and collagen expression is decreased. Moreover fibrin deposition m the lungs of fibrotic PAR 2-/- mice is reduced compared with wild type mice due to differential tissue factor expression in response to bleomycin Taken together these results suggest an important role for PAR 2 in the development of pulmonary fibrosis and the inhibition of the PAR 2 coagulation axis may pro vide a novel therapeutic approach to treat this devastating disease (Am J Pathol 2010 177 2753-2764 DOI 10 2353/ajpath 2010 091107)