Abstract
It is unknown whether impaired barrier function and reduced expression of adherens and tight junction proteins in the airway epithelium of asthmatic patients is cause or consequence of asthma pathogenesis. Here, we test the hypothesis that loss of E-cadherin in airway epithelial cells critically contributes to the pathogenesis of allergic asthma. To this end, we established mice with conditional loss of E-cadherin in the airway epithelium (Cdh1fl/fl Cre+), and compared these to Cre-negative littermates. Naïve mice were examined for lung anatomy and inflammation at several ages, and after House Dust Mite treatment (HDM) in 4 week old mice. Cdh1fl/fl Cre+ mice were viable and displayed no gross abnormalities in lung development. However, pro-inflammatory activation of the airway epithelium was evident from CCL17 and MIP3α production, and inflammatory dendritic cells and eosinophils accumulated in lungs of naïve Cdh1fl/fl Cre+ mice. Cdh1fl/fl Cre+ mice display spontaneous goblet cell metaplasia and hypoplasia of ciliated and secretory airway epithelial cells in the bronchioles. Exposure of 4-week old Cdh1fl/fl Cre+ mice to HDM induced strongly exaggerated eosinophilic airway inflammation compared to Cre- littermates. These data show that airway epithelial loss of E-cadherin induces spontaneous changes characteristic of an asthmatic phenotype, and strongly enhances sensitivity to HDM-induced allergic airway inflammation. Hence, loss of E-cadherin is not merely a consequence of disease, but contributes to asthma pathogenesis, identifying epithelial integrity as a target for novel therapeutic strategies.
- Copyright ©ERS 2015