BACKGROUND:Fine particulate matter (PM2.5) exposure significantly contributes to the development of chronic obstructive pulmonary disease (COPD). However, the underlying mechanisms remain inadequately elucidated, and there is a lack of effective clinical treatments. A combination of five bioactive ingredients derived from the traditional Chinese prescription Bufei Yishen formula (BYF) that is widely accepted for COPD treatment, exhibits bioequivalence with BYF and has been shown to alleviate COPD exacerbation in rat models induced by PM2.5 exposure.
PURPOSE:To investigate the underlying mechanisms of the effective compound combination (ECC) attenuating mitochondrial oxidative stress in COPD progression induced by PM2.5 exposure.
METHODS:The COPD rats were induced by cigarette smoke inhalation and bacterial infection, then exposed to real-time PM2.5 by a whole-body exposure system. The therapeutic efficacy of ECC was assessed by evaluating lung function, pathological changes, levels of oxidative stress, and inflammation. In vitro, the PM2.5-induced human bronchial and alveolar epithelial cells (BEAS-2B and HPAEpiC) were used to explore the underlying mechanisms of ECC against mitochondrial oxidative stress.
RESULTS:Initially, based on the successful establishment of a PM2.5-aggravated COPD rat model, we demonstrated the protective effects of ECC on COPD progression induced by PM2.5 exposure by improving lung function, alleviating pathological injury, and reducing oxidative stress and inflammation. Subsequently, we identified that the inhibitory effects of ECC on mitochondrial oxidative damage, respiratory dysfunction, and fission/fusion imbalance induced by PM2.5 are primarily mediated through SIRT3 activation, both in vivo and in vitro. Mechanically, the deacetylation of FOXO3 at lysine residues 271 and 290 by SIRT3 is crucial for ECC to mitigate mitochondrial oxidative stress during the progression of COPD in response to PM2.5.
CONCLUSION:This study reveals a previously unrecognized mechanism by which ECC acts as an agonist of SIRT3, offering potential therapeutic benefits for patients with COPD who are exposed to PM2.5.