title: 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.
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jill R
authors.initials: JR
authors.lastname: Johnson
authors.forename: Abraham
authors.initials: A
authors.lastname: Roos
authors.forename: Tove
authors.initials: T
authors.lastname: Berg
authors.forename: Magnus
authors.initials: M
authors.lastname: Nord
authors.forename: Jonas
authors.initials: J
authors.lastname: Fuxe
mesh_terms: D056151:Airway Remodeling / Q000276:immunology*; D000485:Allergens / Q000009:adverse effects*; D000818:Animals; D001249:Asthma / Q000473:pathology; D002465:Cell Movement; D002908:Chronic Disease; D058750:Epithelial-Mesenchymal Transition / Q000276:immunology*; D004848:Epithelium / Q000276:immunology / Q000473:pathology; D051379:Mice; D039981:Pyroglyphidae / Q000276:immunology; D012137:Respiratory System / Q000276:immunology / Q000473:pathology*
chemical_list: D000485:Allergens