Free radical generation induces epithelial-to-mesenchymal transition in lung epithelium via a TGF-β1-dependent mechanism
Free radical generation induces epithelial-to-mesenchymal transition in lung epithelium via a TGF-β1-dependent mechanism
复制标题
DOI：
10.1016/j.freeradbiomed.2011.12.020
复制
发表时间：
2012-03-15
影响因子：
7.4
通讯作者：
Fisher, Andrew J.
中科院分区：
文献类型：
--
作者：
Gorowiec, Marta R.;Borthwick, Lee A.;Fisher, Andrew J.
肺实质和气道隔室的纤维化重塑是慢性肺部疾病（如特发性肺纤维化（IPF）和慢性阻塞性肺疾病（COPD））危及生命的器官功能障碍的主要因素。由于转化生长因子- β (tgf - β 1)被认为在疾病发病机制中起关键作用，并且在这些患者的支气管肺泡灌洗（BAL）中也经常检测到氧化应激标志物，因此我们试图研究这两个因素是否可能相互关联。在这里，我们研究了肺上皮氧化应激通过增加tgf - β 1驱动上皮-间质转化（EMT）来促进纤维化修复的假设。我们发现，在400 μ M过氧化氢（H2O2） A549细胞（肺泡上皮模型）的作用下，人原代支气管上皮细胞（PBECs）发生EMT，表现为形态学改变，上皮标志物（E-cadherin和ZO-1）表达减少，间质标志物（vimentin和α -平滑肌肌动蛋白）表达增加，细胞外基质成分分泌增加。同样的氧化应激也会促进tgf - β 1的表达。抑制tgf - β 1信号以及用抗氧化剂如苯基叔丁基硝基酮（PBN）和超氧化物歧化酶3 （SOD3）治疗可以防止氧化应激驱动的emt样变化。干预也抑制了类似emt的变化。本研究确定了肺上皮中氧化应激、tgf - β 1和EMT之间的联系，并强调了抗氧化疗法限制EMT及其对慢性肺部疾病的潜在贡献的潜力。(C) 2012爱思唯尔公司版权所有。
Fibrotic remodelling of lung parenchymal and airway compartments is the major contributor to life-threatening organ dysfunction in chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and Chronic Obstructive Pulmonary Disease (COPD). Since transforming growth factor-beta (TGF-beta 1) is believed to play a key role in disease pathogenesis and markers of oxidative stress are also commonly detected in bronchoalveolar lavage (BAL) from such patients we sought to investigate whether both factors might be interrelated.Here we investigated the hypothesis that oxidative stress to the lung epithelium promotes fibrotic repair by driving epithelial-to-mesenchymal transition (EMT) via the augmentation of TGF-beta 1.We show that in response to 400 mu M hydrogen peroxide (H2O2) A549 cells, used a model for alveolar epithelium, and human primary bronchial epithelial cells (PBECs) undergo EMT displaying morphology changes, decreased expression of epithelial markers (E-cadherin and ZO-1), increased expression of mesenchymal markers (vimentin and alpha-smooth muscle actin) as well as increased secretion of extracelluar matrix components. The same oxidative stress also promotes expression of TGF-beta 1. Inhibition of TGF-beta 1 signalling as well as treatment with antioxidants such as phenyl tert-butylnitrone (PBN) and superoxide dismutase 3 (SOD3) prevent the oxidative stress driven EMT-like changes described above. Interventions also inhibited EMT-like changes.This study identifies a link between oxidative stress, TGF-beta 1 and EMT in lung epithelium and highlights the potential for antioxidant therapies to limit EMT and its potential contribution to chronic lung disease. (C) 2012 Elsevier Inc. All rights reserved.