Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients
Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients
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DOI：
10.1172/jci32526
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发表时间：
2007-11-01
影响因子：
15.9
通讯作者：
Nishimura, Stephen L.
中科院分区：
文献类型：
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作者：
Araya, Jun;Cambier, Stephanie;Nishimura, Stephen L.
鳞状上皮化生（SM）在吸烟者中很常见，并与慢性阻塞性肺疾病（COPD）的气道阻塞有关。COPD气道阻塞的主要机制是小气道壁增厚。我们询问SM是否通过改变COPD中上皮-间质相互作用而积极促进气道壁增厚。使用免疫组化染色，气道形态测定，成纤维细胞培养的肺样本从COPD患者;全基因组分析的体外模型SM;和体外建模的人气道上皮间质相互作用，我们提供的证据表明，SM，通过增加分泌的IL-1 β，诱导邻近气道成纤维细胞的纤维化反应。我们确定了整合素介导的TGF-β激活在放大SM和驱动IL-1 β依赖性促纤维化间充质反应中的关键作用。最后，我们发现SM与COPD的严重程度增加相关，并且气道成纤维细胞TGF-β活化的主要介质整合素α（v）β（8）的成纤维细胞表达与COPD的疾病严重程度和小气道壁增厚相关。我们的研究结果已经确定TGF-β作为COPD的潜在治疗靶点。
Squamous metaplasia (SM) is common in smokers and is associated with airway obstruction in chronic obstructive pulmonary disease (COPD). A major mechanism of airway obstruction in COPD is thickening of the small airway walls. We asked whether SM actively contributes to airway wall thickening through alteration of epithelial-mesenchymal interactions in COPD. Using immunohistochemical staining, airway morphometry, and fibroblast culture of lung samples from COPD patients; genome-wide analysis of an in vitro model of SM; and in vitro modeling of human airway epithelial-mesenchymal interactions, we provide evidence that SM, through the increased secretion of IL-1 beta, induces a fibrotic response in adjacent airway fibroblasts. We identify a pivotal role for integrin-mediated TGF-beta activation in amplifying SM and driving IL-1 beta-dependent profibrotic mesenchymal responses. Finally, we show that SM correlates with increased severity of COPD and that fibroblast expression of the integrin alpha(v)beta(8), which is the major mediator of airway fibroblast TGF-beta activation, correlated with disease severity and small airway wall thickening in COPD. Our findings have identified TGF-beta as a potential therapeutic target for COPD.