Activation of calpain by renin-angiotensin system in pleural mesothelial cells mediates tuberculous pleural fibrosis.
Activation of calpain by renin-angiotensin system in pleural mesothelial cells mediates tuberculous pleural fibrosis.
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胸膜间皮细胞中肾素-血管紧张素系统激活钙蛋白酶介导结核性胸膜纤维化。
DOI：
10.1152/ajplung.00348.2015
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发表时间：
2016-07-01
期刊：
影响因子：
--
通讯作者：
Ma WL
中科院分区：
文献类型：
--
作者：
Yang J;Xiang F;Cai PC;Lu YZ;Xu XX;Yu F;Li FZ;Greer PA;Shi HZ;Zhou Q;Xin JB;Ye H;Su Y;Ma WL
胸膜纤维化的定义是细胞外基质(ECM)成分过度沉积，导致正常胸膜组织结构的破坏。它可以由不同的炎症条件引起，特别是结核性胸膜炎。胸膜间皮细胞(PMC)在胸膜纤维化中起着关键作用。钙蛋白酶是一类钙依赖性内肽酶家族，在细胞外基质重塑中起重要作用。然而，钙蛋白酶在胸膜纤维化中的作用仍不清楚。在本研究中，我们发现结核性胸腔积液(TPE)可诱导胸膜间充质细胞(PMC)中钙蛋白酶的激活，而抑制钙蛋白酶可阻止胸腔积液(TPE)诱导的PMC合成I型胶原和细胞增殖。此外，恶性胸腔积液患者胸腔积液中血管紧张素转换酶水平显著高于恶性胸腔积液患者，且血管紧张素转换酶II可导致胸腔积液中钙蛋白的激活，进而激活PMC中的磷脂酰肌醇3-激酶(PI3K)/AKT/NF-κB信号通路。最后，在结核性胸膜炎患者的胸膜活检标本中，证实了PMC中钙蛋白酶的激活和胶原的沉积。综上所述，这些研究表明，在胸膜纤维化中，Calain被肾素-血管紧张素系统激活，并通过PI3K/Akt/NF-κB信号通路介导TPE诱导的间质细胞I型胶原合成和增殖。PMC中的钙蛋白酶可能是干预结核性胸膜纤维化的新靶点。
Pleural fibrosis is defined as an excessive deposition of extracellular matrix (ECM) components that results in destruction of the normal pleural tissue architecture. It can result from diverse inflammatory conditions, especially tuberculous pleurisy. Pleural mesothelial cells (PMCs) play a pivotal role in pleural fibrosis. Calpain is a family of calcium-dependent endopeptidases, which plays an important role in ECM remodeling. However, the role of calpain in pleural fibrosis remains unknown. In the present study, we found that tuberculous pleural effusion (TPE) induced calpain activation in PMCs and that inhibition of calpain prevented TPE-induced collagen-I synthesis and cell proliferation of PMCs. Moreover, our data revealed that the levels of angiotensin (ANG)-converting enzyme (ACE) were significantly higher in pleural fluid of patients with TPE than those with malignant pleural effusion, and ACE-ANG II in TPE resulted in activation of calpain and subsequent triggering of the phosphatidylinositol 3-kinase (PI3K)/Akt/NF-κB signaling pathway in PMCs. Finally, calpain activation in PMCs and collagen depositions were confirmed in pleural biopsy specimens from patients with tuberculous pleurisy. Together, these studies demonstrated that calpain is activated by renin-angiotensin system in pleural fibrosis and mediates TPE-induced collagen-I synthesis and proliferation of PMCs via the PI3K/Akt/NF-κB signaling pathway. Calpain in PMCs might be a novel target for intervention in tuberculous pleural fibrosis.