Abstract
Background: Effective-component compatibility of Bufei Yishen formula Ⅲ (ECC-BYF Ⅲ) shows positive effects on stable chronic obstructive pulmonary disease (COPD).Purpose: To investigate the mechanisms of ECC-BYF Ⅲ on COPD rats from the aspect of airway epithelial cell senescence.Methods: COPD model rats were treated with ECC-BYF Ⅲ for 8 weeks and the efficacy was evaluated. Cigarette smoke extract (CSE) induced senescence model of airway epithelial cells were treated with ECC-BYF Ⅲ, the related enzymes and proteins involved in oxidative stress and mitophagy were detected.Results: ECC-BYF Ⅲ markedly rescued pulmonary function and histopathological changes, which might be associated with the amelioration of lung senescence, including reduction of malondialdehyde (MDA) and tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and matrix metalloproteinase (MMP)-9, increase of the level of total superoxide dismutase (T-SOD), and decease of p21 level in airway. Furthermore, ECC-BYF Ⅲ suppressed p16, p21 expressions and senescence-associated β-galactosidase (SA-β-Gal) in CSE-induced airway epithelial cells. Moreover, ECC-BYF Ⅲ upregulated the mitophagy-related proteins, including co-localization of TOM20 and LC3B, PINK1, PARK2, and improved mitochondrial function with upregulating mitochondrial mitofusin (Mfn)2 and reducing dynamin-related protein 1 (Drp1) expression. ECC-BYF Ⅲ enhanced the activities of T-SOD and GSH-PX by up-regulating Nrf2, thus inhibiting oxidative stress. After intervention with Nrf2 inhibitor, the regulation effects of ECC-BYF Ⅲ on oxidative stress, mitophagy and senescence in airway epithelial cells were significantly suppressed.Conclusions: ECC-BYF Ⅲ exerts beneficial effects on COPD rats by ameliorating airway epithelial cell senescence, which is mediated by inhibiting oxidative stress and subsequently enhancing mitophagy through activation of Nrf2 signaling.