Imprinting of the COPD airway epithelium for dedifferentiation and mesenchymal transition

Abstract

In chronic obstructive pulmonary disease (COPD), epithelial changes and subepithelial fibrosis are salient features in conducting airways. Epithelial-to-mesenchymal transition (EMT) has been recently suggested in COPD, but the mechanisms and relationship to peribronchial fibrosis remain unclear. We hypothesised that de-differentiation of the COPD respiratory epithelium through EMT could participate in airway fibrosis and thereby, in airway obstruction.Surgical lung tissue and primary broncho-epithelial cultures (in air-liquid interface (ALI)) from 104 patients were assessed for EMT markers. Cell cultures were also assayed for mesenchymal features and for the role of transforming growth factor (TGF)-β1.The bronchial epithelium from COPD patients showed increased vimentin and decreased ZO-1 and E-cadherin expression. Increased vimentin expression correlated with basement membrane thickening and airflow limitation. ALI broncho-epithelial cells from COPD patients also displayed EMT phenotype in up to 2 weeks of culture, were more spindle shaped and released more fibronectin. Targeting TGF-β1 during ALI differentiation prevented vimentin induction and fibronectin release.In COPD, the airway epithelium displays features of de-differentiation towards mesenchymal cells, which correlate with peribronchial fibrosis and airflow limitation, and which are partly due to a TGF-β1-driven epithelial reprogramming. @ERSpublications The COPD airway epithelium is programmed for mesenchymal transition via a TGF-β1-dependent process

Reduced Expiratory Flow Rate among Heavy Smokers Increases Lung Cancer Risk. Results from the National Lung Screening Trial–American College of Radiology Imaging Network Cohort

“…Since 2010, when EMT was first identified in patients with COPD (19), it has been associated with worsening airflow limitation, and has subsequently been reported by three further research groups using surgical samples from patients with or without COPD with lung cancer (20). EMT is considered a precursor to many other epithelial-based cancers, and has been shown to be potentially reversible with immunemodulatory treatment (15).…”

Studies on cell junctions in an ex vivo human lung infection model

“…They were rather described as dots or a short line. Only in primary human bronchiolar epithelial cells or cell lines a continuous band-like structure of ZO-1 as well as occludin was shown [280,281]. In this study, the images are maximum [282,283].…”

Overexpression of farnesoid X receptor in small airways contributes to epithelial to mesenchymal transition and COX-2 expression in chronic obstructive pulmonary disease

“…To the best of our knowledge, this is the first study exploring the role of FXR in EMT in small airways. Since EMT features of airway are found to be associated with the severity of airway limitation (3,4), overexpression of FXR may contributed to airflow limitation in COPD patients through promoting EMT in small airways. Additional studies are needed to further clarify the underlying mechanisms.…”

“…Elevated mesenchymal biomarkers including α-smooth muscle actin (α-SMA), vimentin and collagen type I, as well as decreased epithelial biomarkers E-cadherin, ZO-1 and cytokeratin have been observed in small airway epithelium from COPD patients. Moreover, EMT features of the bronchial epithelium are associated with the severity of airway limitation (3,4), suggesting the involvement of EMT in progression of COPD. The induction of EMT in human bronchial epithelial (HBE) cells was also observed upon the stimulation with cigarette smoke or TGF-β1 in vitro (3,5).…”