Accelerated ageing in COPD: epithelial barrier dysfunction as a driver of abnormal lung tissue repair and remodelling

As our population ages, the prevalence of chronic age-related diseases such as Chronic Obstructive Pulmonary Disease (COPD) rises. Together with age and inherited factors, prolonged exposure to harmful pollutants like cigarette smoke is a major risk factor for COPD. This exposure induces oxidative stress and disrupts the lung epithelium, the protective barrier of our lungs, leading to irreversible damage because of impaired tissue repair in COPD. We investigated how ageing affects the development of COPD, focusing on the lung’s epithelial barrier and the underlying layer with fibroblasts, cells responsible for tissue repair. We explored age-related gene changes in the epithelial barrier and found that the CDH1 gene, which is important for maintaining the epithelial barrier, was lower in older individuals. We next assessed the impact of smoke and observed that epithelial cells from younger and older non-smokers do equally well in barrier formation, those from former smokers, particularly with severe COPD, show persistent impairment and poor recovery from smoke-induced epithelial damage. When examining the regenerative ability of epithelial cells using a 3D mini-organs model, we observed abnormalities in cells from severe COPD patients. Detailed gene studies suggest an impaired specialization/differentiation capacity of the cells. Exploring the effect of age on fibroblast responses, we observed that older individuals’ fibroblasts are more inflammatory and less capable of supporting tissue repair. We identified key genes associated with fibroblast ageing and potential anti-ageing treatment strategies. The thesis highlights how ageing affects the lung epithelial barrier and fibroblast responses, contributing to COPD development.