Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
PLoS One. 2011 Jan 20;6(1):e16175. doi: 10.1371/journal.pone.0016175.
Chronic allergic asthma is characterized by Th2-polarized inflammation and leads to airway remodeling and fibrosis but the mechanisms involved are not clear. To determine whether epithelial-mesenchymal transition contributes to airway remodeling in asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM) extract for up to 15 consecutive weeks. We report that respiratory exposure to HDM led to significant airway inflammation and thickening of the smooth muscle layer in the wall of the large airways. Transforming growth factor beta-1 (TGF-β1) levels increased in mouse airways while epithelial cells lost expression of E-cadherin and occludin and gained expression of the mesenchymal proteins vimentin, alpha-smooth muscle actin (α-SMA) and pro-collagen I. We also observed increased expression and nuclear translocation of Snail1, a transcriptional repressor of E-cadherin and a potent inducer of EMT, in the airway epithelial cells of HDM-exposed mice. Furthermore, fate-mapping studies revealed migration of airway epithelial cells into the sub-epithelial regions of the airway wall. These results show the contribution of EMT to airway remodeling in chronic asthma-like inflammation and suggest that Th2-polarized airway inflammation can trigger invasion of epithelial cells into the subepithelial regions of the airway wall where they contribute to fibrosis, demonstrating a previously unknown plasticity of the airway epithelium in allergic airway disease.
慢性过敏性哮喘的特征是 Th2 极化炎症，导致气道重塑和纤维化，但涉及的机制尚不清楚。为了确定上皮-间充质转化是否有助于哮喘中的气道重塑，我们通过鼻内给予屋尘螨（HDM）提取物长达 15 周连续诱导小鼠过敏性气道炎症。我们报告说，呼吸暴露于 HDM 导致大气道壁中的气道炎症和平滑肌层增厚明显。转化生长因子β-1（TGF-β1）水平在小鼠气道中增加，而上皮细胞失去 E-钙粘蛋白和闭合蛋白的表达，并获得间充质蛋白波形蛋白、α-平滑肌肌动蛋白（α-SMA）和前胶原 I 的表达。我们还观察到，在暴露于 HDM 的小鼠气道上皮细胞中，E-钙粘蛋白的转录抑制因子和 EMT 的强诱导剂 Snail1 的表达增加，并发生核易位。此外，命运图谱研究显示气道上皮细胞向气道壁的粘膜下区域迁移。这些结果表明 EMT 对慢性哮喘样炎症中的气道重塑有贡献，并表明 Th2 极化的气道炎症可以触发上皮细胞侵入气道壁的粘膜下区域，从而导致纤维化，证明了过敏性气道疾病中气道上皮的以前未知的可塑性。
