Department of Biochemistry, Faculty of Medicine, University of Giessen Lung Center, Friedrichstrasse 24, 35392 Giessen, Germany.
Am J Respir Crit Care Med. 2011 Jun 15;183(12):1703-14. doi: 10.1164/rccm.201009-1479OC. Epub 2011 Mar 11.
Activation of the coagulation cascade has been demonstrated in pulmonary fibrosis. In addition to its procoagulant function, various coagulation proteases exhibit cellular effects that may also contribute to fibrotic processes in the lung.
To investigate the importance of protease-activated receptor (PAR)-2 and its activators, coagulation factor VIIa (FVIIa)/tissue factor (TF), in the development of idiopathic pulmonary fibrosis (IPF).
Expression and localization of PAR-2 and its activators were examined in IPF lung tissue. The ability of PAR-2 to mediate various cellular processes was studied in vitro.
Expression of PAR-2 was strongly elevated in IPF lungs and was attributable to alveolar type II cells and fibroblasts/myofibroblasts. Transforming growth factor-β(1), a key profibrotic cytokine, considerably enhanced PAR-2 expression in human lung fibroblasts. FVIIa stimulated proliferation of human lung fibroblasts and extracellular matrix production in a PAR-2-dependent manner, but did not initiate differentiation of fibroblasts into myofibroblasts. PAR-2/FVIIa-driven mitogenic activities were mediated via the p44/42 mitogen-activated protein kinase pathway and were independent of factor Xa and thrombin production. Proproliferative properties of FVIIa were markedly potentiated in the presence of TF and abrogated by TF antisense oligonucleotides. Hyperplastic alveolar type II cells overlying fibroblastic foci were found to be the source of FVII in IPF lungs. Moreover, TF colocalized with PAR-2 on fibroblasts/myofibroblasts in IPF lungs.
The PAR-2/TF/FVIIa axis may contribute to the development of pulmonary fibrosis; thus, interference with this pathway confers novel therapeutic potential for the treatment of IPF.
已在肺纤维化中证实凝血级联的激活。除其促凝功能外，各种凝血蛋白酶还具有细胞作用，这也可能有助于肺部的纤维化过程。
研究蛋白酶激活受体（PAR）-2及其激活剂凝血因子 VIIa（FVIIa）/组织因子（TF）在特发性肺纤维化（IPF）发展中的重要性。
研究 IPF 肺组织中 PAR-2及其激活剂的表达和定位。在体外研究 PAR-2 介导各种细胞过程的能力。
PAR-2 的表达在 IPF 肺中强烈升高，归因于肺泡 II 型细胞和成纤维细胞/肌成纤维细胞。转化生长因子-β（1），一种关键的促纤维化细胞因子，可大大增强人肺成纤维细胞中 PAR-2 的表达。FVIIa 以 PAR-2 依赖的方式刺激人肺成纤维细胞的增殖和细胞外基质的产生，但不会启动成纤维细胞向肌成纤维细胞的分化。PAR-2/FVIIa 驱动的有丝分裂活性是通过 p44/42 丝裂原激活蛋白激酶途径介导的，与因子 Xa 和凝血酶的产生无关。TF 存在时，FVIIa 的促增殖作用明显增强，而 TF 反义寡核苷酸则消除了这种作用。在 IPF 肺中，发现增生性肺泡 II 型细胞覆盖在成纤维细胞灶上是 FVII 的来源。此外，TF 与 IPF 肺中成纤维细胞/肌成纤维细胞上的 PAR-2 共定位。
PAR-2/TF/FVIIa 轴可能有助于肺纤维化的发展；因此，干扰该途径为治疗特发性肺纤维化提供了新的治疗潜力。
