Altered expression of tight junction molecules in alveolar septa in lung injury and fibrosis
Altered expression of tight junction molecules in alveolar septa in lung injury and fibrosis
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DOI：
10.1152/ajplung.00349.2010
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发表时间：
2012-01-01
影响因子：
4.9
通讯作者：
Nukiwa, Toshihiro
中科院分区：
文献类型：
--
作者：
Ohta, Hiromitsu;Chiba, Shigeki;Nukiwa, Toshihiro
吴晓刚，王晓刚.肺损伤和纤维化时肺泡间隔紧密连接分子表达的改变。美国生理学杂志肺细胞分子生理学302：L193-L205，2012年。首次发表于2011年10月14日; doi：10.1152/ajplung.00349.2010.-肺泡屏障功能障碍是肺损伤和随后的纤维化发展的关键因素，但其潜在的分子机制仍知之甚少。为了阐明紧密连接在肺损伤和纤维化中的致病作用，我们研究了紧密连接的主要成分--紧密连接蛋白在肺纤维化疾病模型肺中的表达改变。在24种已知的claudin中，claudin-1、claudin-3、claudin-4、claudin-7和claudin-10被鉴定为气道紧密连接的组分。Claudin-5和claudin-18被鉴定为肺泡紧密连接的组成部分，分别在内皮细胞和肺泡上皮细胞中表达。在实验性博莱霉素诱导的肺损伤中，编码紧密连接蛋白的mRNA水平降低，特别是claudin-18的水平。博莱霉素腹腔灌注后14天，纤维化病变中上皮紧密连接的完整性受到干扰。结果提示，博莱霉素主要损伤肺泡上皮细胞，损害肺泡屏障功能。此外，我们分析了转化生长因子-β（TGF-β）的影响，肺纤维化的一个关键介质，是博来霉素诱导的肺损伤后上调，在体外的紧密连接。TGF-β的加入降低了人脐静脉内皮细胞中claudin-5的表达，并破坏了上皮细胞的紧密连接（A549）。这些结果表明，博莱霉素诱导的肺损伤引起紧密连接的致病性改变，这种改变似乎是由TGF-β诱导的。
Ohta H, Chiba S, Ebina M, Furuse M, Nukiwa T. Altered expression of tight junction molecules in alveolar septa in lung injury and fibrosis. Am J Physiol Lung Cell Mol Physiol 302: L193-L205, 2012. First published October 14, 2011; doi:10.1152/ajplung.00349.2010.-The dysfunction of alveolar barriers is a critical factor in the development of lung injury and subsequent fibrosis, but the underlying molecular mechanisms remain poorly understood. To clarify the pathogenic roles of tight junctions in lung injury and fibrosis, we examined the altered expression of claudins, the major components of tight junctions, in the lungs of disease models with pulmonary fibrosis. Among the 24 known claudins, claudin-1, claudin-3, claudin-4, claudin-7, and claudin-10 were identified as components of airway tight junctions. Claudin-5 and claudin-18 were identified as components of alveolar tight junctions and were expressed in endothelial and alveolar epithelial cells, respectively. In experimental bleomycin-induced lung injury, the levels of mRNA encoding tight junction proteins were reduced, particularly those of claudin-18. The integrity of the epithelial tight junctions was disturbed in the fibrotic lesions 14 days after the intraperitoneal instillation of bleomycin. These results suggest that bleomycin mainly injured alveolar epithelial cells and impaired alveolar barrier function. In addition, we analyzed the influence of transforming growth factor-beta (TGF-beta), a critical mediator of pulmonary fibrosis that is upregulated after bleomycin-induced lung injury, on tight junctions in vitro. The addition of TGF-beta decreased the expression of claudin-5 in human umbilical vein endothelial cells and disrupted the tight junctions of epithelial cells (A549). These results suggest that bleomycin-induced lung injury causes pathogenic alterations in tight junctions and that such alterations seem to be induced by TGF-beta