Melatonin ameliorates PM2.5-induced airway inflammation and apoptosis by PERK/eIF2α/ATF4/CHOP in chronic obstructive pulmonary disease mice.

Fine particulate matter (PM2.5) has been reported to exacerbate chronic airway inflammation, contributing to progression and acute exacerbation of chronic obstructive pulmonary disease (COPD). Persistent activated endoplasmic reticulum (ER) stress-related PERK/eIF2α/ATF4/CHOP pathway is critical in driving inflammation and cell death in a variety of inflammatory diseases. Melatonin (MEL) is well-recognized for its broad biological activities, such as anti-oxidative and anti-inflammatory effects However, the exact role of ER stress-related pathway and MEL in PM2.5-induced airway inflammation and apoptosis in COPD has not yet been elucidated. Therefore, we constructed the COPD mice model by cigarette smoke (CS) exposure to evaluate the mechanism by which PM2.5 exacerbate the development of COPD and the protective role of MEL. Results indicated that PM2.5 significantly impair lung function, disrupt emphysema, exacerbate inflammation and apoptosis and intensify the PERK/eIF2α/ATF4/CHOP pathway in COPD mice. Moreover, these changes caused by PM2.5 could be mitigated by MEL. In vitro, PM2.5 exposure notably reduced cell viability and triggered inflammation and apoptosis in BEAS-2B cells induced by cigarette smoke extract (CSE). These effects were reversed by the ER stress inhibitor 4-phenylbutyric acid (4-PBA), with MEL demonstrating similar effect. These findings demonstrate that PM2.5 aggravates airway inflammation and apoptosis via activating ER stress-related PERK/eIF2α/ATF4/CHOP pathways in COPD, which could be significantly restored by MEL.