PM2.5 Exacerbates Airway Inflammation and Epithelial Barrier Disruption in Chronic Obstructive Pulmonary Disease Mice Through the RAGE‐Dependent PERK/eIF2α/ATF4/CHOP Pathway

Long‐term exposure to a PM2.5 environment can trigger inflammatory responses that lead to tissue destruction and chronic obstructive pulmonary disease (COPD). Endoplasmic reticulum (ER) stress is an important mechanism involved in the development of COPD. The receptor for advanced glycation end products (RAGE) is highly expressed in the lungs and is associated with the occurrence of respiratory diseases. However, the effects of PM2.5 on exacerbating COPD and whether it regulates ER stress remain unclear and require further investigation. Therefore, a mouse model of COPD was developed through exposure to cigarette smoke to investigate how PM2.5 exacerbates the progression of COPD and the negative effects associated with RAGE. The findings revealed that PM2.5 markedly disrupted lung function, exacerbated emphysema, increased inflammation, apoptosis, and epithelial tight junction damage; and activated the PERK/eIF2α/ATF4/CHOP pathway in mice with COPD. Additionally, the detrimental effects induced by PM2.5 were alleviated by the RAGE inhibitor FPS‐ZM1 and the ER stress modulator 4‐PBA. These results indicated that PM2.5 exacerbates inflammation, apoptosis, and epithelial tight junction disruption by activating the PERK/eIF2α/ATF4/CHOP pathway in mice with COPD. This effect can be partially reversed by inhibiting RAGE expression.