Hydrogen sulfide attenuates PM2.5-induced COPD by inhibiting cellular senescence via the Klotho/Parkin-mediated mitophagy signaling pathway
Ying Wang, Guoqing Han, Jin Yang, Lixiang Xue, Yahong Chen
Abstract
Fine particulate matter (PM2.5), an atmospheric pollutant, plays a crucial role in mediating the occurrence of chronic obstructive pulmonary disease (COPD). Hydrogen sulfide (H 2 S) has shown therapeutic potential in countering COPD, but the underlying mechanisms remain elusive. This study aimed to elucidate the potential mechanisms of H 2 S in inhibiting cellular senescence and combating the progression of COPD. In this study, mouse and cell models were initially established by pretreating with PM, PM2.5, and NaHS. It was showed that increased expressions of p16, p21, and β-gal positive cells, along with elevated inflammatory and oxidative stress markers and reduced antioxidant markers, could be observed in COPD patients as well as in PM2.5-induced cell and mouse models, correlating with decreased endogenous H 2 S levels. Pre-treatment with NaHS reversed these effects, enhancing Klotho expression, inhibiting IGF-1R, and activating the Parkin- dependent mitophagy pathway, which significantly mitigated airway inflammation and emphysema. Klotho silencing in BEAS-2B cells exacerbated the PM2.5-induced damage and diminished the protective effects of NaHS, confirming the link between Klotho and the downstream Parkin-dependent mitophagy pathway. Our findings suggest that H 2 S mitigates PM2.5-induced senescence in airway epithelial cells by modulating the Klotho/IGF-1R/Parkin-dependent mitophagy pathway, thereby alleviating airway inflammation and emphysema. This provides a foundation for devising innovative treatment approaches for COPD and mitigating the health effects of atmospheric pollution. Schematic representation of the potential mechanism of H 2 S against PM2.5-mediated cellular senescence via the Klotho/IGF-1R/Parkin-mediated mitophagy pathway in airway epithelial cells. (Note: Red lines represent the relationships clarified in this research.) • Cellular senescence plays a role in the progression of COPD. • H 2 S protects against PM2.5-induced emphysema and airway inflammation through reducing oxidative-mediated cellular senescence. • H 2 S mitigates cellular senescence by activating Parkin-dependent mitophagy signaling pathway. • H 2 S regulates Parkin-dependent mitophagy through targeting Klotho.