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CXCR7 attenuates the TGF-β-induced endothelial-to-mesenchymal transition and pulmonary fibrosis
Molecular BioSystems Pub Date : 2017-08-10 00:00:00 , DOI: 10.1039/c7mb00247e
Shuhong Guan 1, 2, 3, 4 , Jun Zhou 1, 2, 3, 4
Affiliation  

Lung fibrosis is a progressive and often fatal lung disease characterized by fibroblast proliferation and excessive deposition of extracellular matrix in the lungs. The chemokine receptor CXCR7 has been shown to control cell adhesion, migration and proliferation by regulating the epithelial-to-mesenchymal transition (EMT), but the role of CXCR7 in regulating the endothelial-to-mesenchymal transition (EndMT) and lung fibrosis remains largely unclear. In this study, we investigated the interrelation of CXCR7 and TGF-β, a crucial player in lung fibrogenesis. We report herein that CXCR7 expression is significantly increased in animal models of TGF-β1-induced pulmonary fibrosis and in TGF-β1-treated endothelial cells. TGF-β1 up-regulates CXCR7 expression in a Smad2/3-dependent manner in endothelial cells. The overexpression of CXCR7 effectively attenuates TGF-β1-induced EndMT in lung endothelial cells, whereas CXCR7 knockdown in endothelial cells further promotes TGF-β1-induced EndMT. Mechanically, CXCR7 attenuates EndMT by inhibiting the Jag1–Notch pathway. CXCR7 overexpression in mice also results in a significant enhancement in endothelial markers and a decrease in mesenchymal markers, indicating a decreased susceptibility to TGF-β1-induced lung fibrosis and deposition of extracellular matrix and collagen. These data suggest that CXCR7 upregulation induced by TGF-β is a feedback mechanism to regulate TGF-β-induced EndMT and pulmonary fibrosis.

中文翻译:

CXCR7减弱了TGF-β诱导的内皮向间充质转化和肺纤维化

肺纤维化是一种进行性且通常是致命的肺部疾病,其特征在于成纤维细胞增殖和肺中细胞外基质的过多沉积。已显示趋化因子受体CXCR7通过调节上皮向间充质转化(EMT)来控制细胞粘附,迁移和增殖,但是CXCR7在调节内皮向间充质转化(EndMT)和肺纤维化中的作用仍然很大不清楚。在这项研究中,我们调查了CXCR7和TGF-β(肺纤维化的关键参与者)之间的相互关系。我们在此报告,在TGF-β1诱导的肺纤维化的动物模型和TGF-β1处理的内皮细胞中,CXCR7表达显着增加。TGF-β1以Smad2 / 3依赖性方式在内皮细胞中上调CXCR7表达。CXCR7的过表达有效地减弱了肺内皮细胞中TGF-β1诱导的EndMT,而内皮细胞中CXCR7的敲低进一步促进了TGF-β1诱导的EndMT。在机械上,CXCR7通过抑制Jag1-Notch途径来减弱EndMT。小鼠中的CXCR7过表达还导致内皮标记物显着增强和间充质标记物减少,表明对TGF-β1诱导的肺纤维化的敏感性降低以及细胞外基质和胶原蛋白的沉积。这些数据表明,TGF-β诱导的CXCR7上调是调节TGF-β诱导的EndMT和肺纤维化的一种反馈机制。CXCR7通过抑制Jag1-Notch途径来减弱EndMT。小鼠中的CXCR7过表达还导致内皮标记物显着增强和间充质标记物减少,表明对TGF-β1诱导的肺纤维化的敏感性降低以及细胞外基质和胶原蛋白的沉积。这些数据表明,TGF-β诱导的CXCR7上调是调节TGF-β诱导的EndMT和肺纤维化的一种反馈机制。CXCR7通过抑制Jag1-Notch途径来减弱EndMT。小鼠中的CXCR7过表达还导致内皮标记物显着增强和间充质标记物减少,表明对TGF-β1诱导的肺纤维化的敏感性降低以及细胞外基质和胶原蛋白的沉积。这些数据表明,TGF-β诱导的CXCR7上调是调节TGF-β诱导的EndMT和肺纤维化的一种反馈机制。
更新日期:2017-08-18
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