Inhibition of BMP activity protects epithelial barrier function in lung injury
Inhibition of BMP activity protects epithelial barrier function in lung injury
复制标题
DOI：
10.1002/path.4215
复制
发表时间：
2013-09-01
影响因子：
7.3
通讯作者：
Moser, Martin
中科院分区：
文献类型：
--
作者：
Helbing, Thomas;Herold, Eva-Maria;Moser, Martin
上皮损伤是肺部疾病的重要发现，并伴有上皮屏障功能的破坏，导致肺水肿和炎症。受伤的上皮细胞失去其特性并获得间质特征，这是一种有助于损伤后肺重塑的表型开关。在这里，我们研究了骨形态发生蛋白（BMP）信号传导，特别是BMP2和BMP调节剂BMPER在损伤肺上皮中的作用。体外和体内肺上皮损伤后，BMP活性增加，反映为Smad1/5-Id1轴上调。BMP家族的两个成员，BMP2和BMPER，具有相反的作用。BMP2在上皮损伤后上调，通过smad1 /5- id1依赖性E-cadherin下调介导，导致上皮功能障碍和高通透性。相比之下，损伤后BMPER表达降低，这反过来又损害了上皮的完整性，其特征是体外和体内e -钙粘蛋白和上皮渗漏减少。高水平的BMPER可拮抗BMP2-Smad5-Id1信号传导，阻止bmp2介导的e -钙粘蛋白和高通透性的降低，表明BMPER可恢复上皮稳态。支持这一观点的是，LDN193189对BMP信号的药理抑制阻止了e -钙粘蛋白的减少和上皮屏障功能的破坏。抑制过度的BMP激活可能是恢复肺损伤后上皮完整性和防止上皮屏障功能破坏的新途径。版权所有(c) 2013大不列颠和爱尔兰病理学会。约翰·威利父子有限公司出版。
Epithelial injury is a central finding in pulmonary disease and is accompanied by disruption of epithelial barrier function, leading to pulmonary oedema and inflammation. Injured epithelial cells lose their properties and gain mesenchymal characteristics, a phenotypic switch that contributes to lung remodelling after injury. Here we studied bone morphogenetic protein (BMP) signalling and, in particular, the role of BMP2 and the BMP modulator BMPER in injured lung epithelium. Increased BMP activity, reflected by up-regulation of the Smad1/5-Id1 axis, is detected after injury of lung epithelium in vitro and in vivo. Two members of the BMP family, BMP2 and BMPER, have opposing effects. BMP2 is up-regulated after epithelial injury and causes epithelial dysfunction and hyperpermeability, mediated by the Smad1/5-Id1-dependent down-regulation of E-cadherin. In contrast, BMPER expression is decreased following injury, which in turn impairs epithelial integrity, characterized by reduction of E-cadherin and epithelial leakage in vitro and in vivo. High levels of BMPER antagonized BMP2-Smad5-Id1 signalling and prevented BMP2-mediated decrease of E-cadherin and hyperpermeability, suggesting that BMPER restores epithelial homeostasis. Supporting this notion, pharmacological inhibition of BMP signalling by LDN193189 prevented reduction of E-cadherin and disruption of epithelial barrier function. Inhibition of excessive BMP activation could be a new approach to restore epithelial integrity and prevent disruption of epithelial barrier function after lung injury. Copyright (c) 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.