Shi Meng, Liu Kai, Li Xin, Zeng Xiao-Li, Liu Xiao-Ju
The First school of Clinical Medicine, Lanzhou University, Lanzhou 730000, China.
The First school of Clinical Medicine, Lanzhou University, Lanzhou 730000, China; The First Hospital of Lanzhou University, Lanzhou 730000, China.
Toxicol Appl Pharmacol. 2025 Jun;499:117314. doi: 10.1016/j.taap.2025.117314. Epub 2025 Mar 26.
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.
据报道，细颗粒物（PM2.5）会加剧慢性气道炎症，导致慢性阻塞性肺疾病（COPD）的进展和急性加重。持续激活的内质网（ER）应激相关的PERK/eIF2α/ATF4/CHOP通路在多种炎症性疾病中驱动炎症和细胞死亡方面至关重要。褪黑素（MEL）因其广泛的生物学活性，如抗氧化和抗炎作用而广为人知。然而，ER应激相关通路和MEL在PM2.5诱导的COPD气道炎症和细胞凋亡中的确切作用尚未阐明。因此，我们通过香烟烟雾（CS）暴露构建了COPD小鼠模型，以评估PM2.5加剧COPD发展的机制以及MEL的保护作用。结果表明，PM2.5显著损害COPD小鼠的肺功能，破坏肺气肿，加剧炎症和细胞凋亡，并增强PERK/eIF2α/ATF4/CHOP通路。此外，PM2.5引起的这些变化可被MEL减轻。在体外，PM2.5暴露显著降低了香烟烟雾提取物（CSE）诱导的BEAS-2B细胞的活力，并引发炎症和细胞凋亡。内质网应激抑制剂4-苯基丁酸（4-PBA）可逆转这些作用，MEL也表现出类似的效果。这些发现表明，PM2.5通过激活COPD中内质网应激相关的PERK/eIF2α/ATF4/CHOP通路加剧气道炎症和细胞凋亡，而MEL可显著恢复这些作用。
