Temporal Evolution of Alveolar Epithelial Cell Dysfunction Induced by Cigarette Smoke in Chronic Obstructive Pulmonary Disease and the Protective Role of SIRT1

Background Chronic obstructive pulmonary disease (COPD) is characterized by pathological alterations including alveolar structure destruction and small airway remodeling. However, the dynamic evolution of alveolar structural damage from the early to advanced stages of COPD remains to be fully elucidated. Meanwhile, SIRT1, a critical regulator of metabolism and cellular stress, warrants further investigation for its potential role in early intervention of COPD. Methods This study set out to track how alveolar epithelial cells change as COPD develops from early to advanced stages, using cigarette smoke (CS) as the trigger. We wanted to see what role SIRT1 plays in this entire process. Results By establishing a mouse COPD model induced by CS combined with lipopolysaccharide (LPS), and utilizing alveolar epithelial cell-specific SIRT1 gain- and loss-of-function models, we found that during the early stage of CS exposure (2 weeks), aberrant proliferative repair of type II alveolar epithelial cells (AT2) serves as a key driver. SIRT1 activation was able to ameliorate this abnormal proliferative repair in AT2, thereby improving lung function. Conclusions Our study shows that at 2 weeks, the number and function of alveolar epithelial cells remained normal. After 4 weeks, however, the number of alveolar epithelial cells decreased, and normal function was gradually lost. Concurrently, the marker for alveolar intermediate cells, KRT8, remained unchanged, suggesting that these intermediate cells may have lost their normal differentiation capacity at this stage. Our work shows that SIRT1 plays a crucial protective role against CS-induced COPD. It seems to work by shielding alveolar epithelial cells from death (apoptosis), dialing down inflammation, helping fix the leaky alveolar barrier, and importantly, by encouraging AT2 cells to properly differentiate into type I cells. So, targeting SIRT1 emerges as a promising strategy. The idea would be to rescue the function and fate of alveolar epithelial cells, which could potentially slow down or improve the course of COPD.