The memory of airway epithelium damage in smokers and COPD patients

Rationale Chronic obstructive pulmonary disease (COPD) is a devastating and mostly irreversible lung disease. In COPD, the bronchial epithelium displays several structural and functional abnormalities affecting barrier integrity, cell polarity, and differentiation, as well as epithelial-to-mesenchymal transition and inflammation. Although COPD displays mostly irreversible changes, the (ir)reversible nature of epithelium pathology ex vivo remains poorly known and was the aim of this study. Methods The persistence of COPD epithelium abnormalities was addressed in long-term (10 weeks) primary cultures of air/liquid interface-reconstituted airway epithelium from non-smoker controls, smoker controls, and COPD patients. Barrier function, epithelial polarity, cell commitment, epithelial-to-mesenchymal transition and inflammation were assessed in vitro , and certain features were compared in situ to the native epithelium. The role of inflammation was explored by stimulating cultures with a cytokine mix consisting of TNF-α, IL-6 and IL-1β. Measurements and main results Almost all epithelial defects (barrier dysfunction, impaired polarity, lineage abnormalities) observed in cells from smokers and COPD patients persisted in vitro up to week 10, except IL-8/CXCL-8 release and epithelial-to-mesenchymal transition which declined over time. Cell lineage and polarity impairments matched abnormalities observed in situ in the surgical samples from which the in vitro epithelium was derived. Cytokine treatment induced COPD-like changes and, in COPD cells, reactivated epithelial-to-mesenchymal transition. Conclusions The airway epithelium from smokers and COPD patients displays a memory of its native state and previous injuries by cigarette smoking, which is multidimensional and sustained for extended periods of time.