Epithelial to mesenchymal transition in the airway epithelium from copd patients: correlation to disease severity

Rationale: In chronic obstructive pulmonary disease (COPD), epithelial changes and subepithelial fibrosis are salient features in the airways. Epithelial to mesenchymal transition (EMT) has been suggested in COPD, mainly in alveolar epithelial cells. Objectives: To evaluate the presence of EMT in the airways and primary air-liquid interface cultures of bronchial epithelial cells (ALI-HBEC) from COPD patients, as compared to controls. Methods: Surgical lung tissue of COPD and control patients (n=49) and ALI-HBEC cultures (n=57) were assessed for EMT markers by immunohistochemistry, western blot and real-time qPCR. Mesenchymal functionalities of ALI-HBEC were assayed through fibronectin release and wound repair. Measurements and main results: The bronchial epithelium from COPD patients, as compared to non-smokers and smokers without COPD, showed increased vimentin expression in large (p=0.002 for severe COPD versus non-smokers) and small airways correlated with airway obstruction (FEV1, FEV1/VC ratio and DLCO). In addition, epithelial E-cadherin and zonula occludens-1 were decreased in large airways. Increased epithelial vimentin expression correlated to subepithelial deposition and basement membrane thickness in imaging of COPD airway tissue thick slices. In addition, the COPD bronchial epithelium displayed similar features (upregulated vimentin, decreased E-cadherin/ZO-1) in vitro, which were also correlated to lung function. Moreover, COPD ALI-HBEC showed mesenchymal functions such as extra-cellular production of fibronectin and impaired migration during wound repair. Conclusions: The bronchial epithelium from COPD patients displays EMT features in lung tissue, which correlates to disease severity and which are recapitulated in primary cultures in ALI conditions. We propose that this abnormal epithelial programming contributes to peribronchial fibrosis in COPD.