Chronic Respiratory Aeroallergen Exposure in Mice Induces Epithelial-Mesenchymal Transition in the Large Airways

Abstract

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.

Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype

“…Other epithelial cells co-expressing vimentin were found in the subepithelial region. These results suggest that EMT is implicated in the bronchial remodelling associated with asthma [129]. This is in agreement with previous reports demonstrating that exposure of epithelial cells to proteolytically active allergens such as Der p 1, a major mite allergen [64,130], or to some pollen allergens [131] induced the degradation of the epithelium.…”

“…Yet in combination with TGF-b, it enhances the expression of EMT markers. These results highlight the importance of TGF-b in EMT in asthma [64,129] and elevated levels of TGF-b have been reported in BAL and bronchial biopsies of asthmatic patients [132,133]. The increase of TGF-b correlates with airflow obstruction and airway wall thickening, and is not changed despite oral treatment with corticosteroids [134,135].…”

“…With the aim of identifying EMT in vivo, JOHNSON et al [129] have developed a murine transgenic model in which airway epithelial cells express the lac-Z reporter gene. After 5 days of exposure to house dust mite allergen epithelial cells underwent EMT, co-expressed the protein S100A4 and accumulated in the smooth muscle.…”

Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases

“…90,91 Different reports suggest that EMT is linked to airway remodeling in asthma. 70,92 Interestingly, EMT is regulated by the Wnt/β-catenin and the noncanonical Wnt signaling pathway. [93][94][95] Also in the lung, Wnt signaling is involved in the regulation of EMT.…”

Eosinophils Promote Epithelial To Mesenchymal Transition Of Bronchial Epithelial Cells

“…Hackett et al suggested that the number of airway epithelial cells undergoing EMT is enhanced and that the process of epithelial repairs is dysregulated in bronchial asthma [14]. Johnson et al reported that house dust mite exposure induces EMT in large airways in mice [15]. These findings suggest that TGF-b1 released by eosinophils may induce EMT leading to airway remodelling.…”