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蛋白酶激活受体(PAR)-1 和 -3 驱动肺泡上皮细胞的上皮-间充质转化 - 在肺纤维化中的潜在作用。

Protease-activated receptors (PAR)-1 and -3 drive epithelial-mesenchymal transition of alveolar epithelial cells - potential role in lung fibrosis.

机构信息

Department of Biochemistry, University of Giessen Lung Center, Friedrichstrasse 24, Giessen, Germany.

出版信息

Thromb Haemost. 2013 Aug;110(2):295-307. doi: 10.1160/TH12-11-0854. Epub 2013 Jun 6.

Abstract

Extravascular activation of the coagulation cascade in the lung is commonly observed in pulmonary fibrosis. Coagulation proteases may exert profibrotic cellular effects via protease-activated receptors (PARs)-1 and -2. Here, we investigated the potential role of two other members of the PAR family, namely PAR-3 and PAR-4, in the pathobiology of lung fibrosis. Elevated expression of PAR-3, but not PAR-4, was detected in the lungs of idiopathic pulmonary fibrosis (IPF) patients and in bleomycin-induced lung fibrosis in mice. Increased PAR-3 expression in fibrotic lungs was mainly attributable to alveolar type II (ATII) cells. Stimulation of primary mouse ATII, MLE15 and A549 cells with thrombin (FIIa) - that may activate PAR-1, PAR-3 and PAR-4 - induced epithelial-mesenchymal transition (EMT), a process that has been suggested to be a possible mechanism underlying the expanded (myo)fibroblast pool in lung fibrosis. EMT was evidenced by morphological alterations, expression changes of epithelial and mesenchymal phenotype markers, and functional changes. Single knockdown of FIIa receptors, PAR-1, PAR-3, or PAR-4, had no major impact on FIIa-induced EMT. Simultaneous depletion of PAR-1 and PAR-3, however, almost completely inhibited this process, whereas only a partial effect on FIIa-mediated EMT was observed when PAR-1 and PAR-4, or PAR-3 and PAR-4 were knocked down. PAR-1 and PAR-3 co-localise within ATII cells with both being predominantely plasma membrane associated. In conclusion, our study indicates that PARs synergise to mediate FIIa-induced EMT and provides first evidence that PAR-3 via its ability to potentiate FIIa-triggered EMT could potentially contribute to the pathogenesis of pulmonary fibrosis.

摘要

血管外凝血级联在肺部的激活在肺纤维化中很常见。凝血蛋白酶可能通过蛋白酶激活受体 (PARs)-1 和 -2 发挥促纤维化细胞作用。在这里,我们研究了 PAR 家族的另外两个成员,即 PAR-3 和 PAR-4,在肺纤维化发病机制中的潜在作用。特发性肺纤维化 (IPF) 患者的肺部和博莱霉素诱导的小鼠肺纤维化中检测到 PAR-3 的表达升高,而 PAR-4 的表达升高。纤维化肺中 PAR-3 表达的增加主要归因于肺泡 II 型 (ATII) 细胞。凝血酶 (FIIa)-可能激活 PAR-1、PAR-3 和 PAR-4-刺激原代小鼠 ATII、MLE15 和 A549 细胞可诱导上皮-间充质转化 (EMT),这一过程被认为是肺纤维化中扩大的 (肌成纤维细胞) 池的可能机制。EMT 通过形态改变、上皮和间充质表型标志物的表达变化以及功能变化来证明。FIIa 受体、PAR-1、PAR-3 或 PAR-4 的单一敲除对 FIIa 诱导的 EMT 没有重大影响。然而,PAR-1 和 PAR-3 的同时耗竭几乎完全抑制了这一过程,而当 PAR-1 和 PAR-4 或 PAR-3 和 PAR-4 被敲除时,对 FIIa 介导的 EMT 仅观察到部分作用。PAR-1 和 PAR-3 在 ATII 细胞内共定位,两者主要与质膜相关。总之,我们的研究表明 PAR 协同作用介导 FIIa 诱导的 EMT,并首次提供证据表明 PAR-3 通过其增强 FIIa 触发的 EMT 的能力可能有助于肺纤维化的发病机制。

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