Bryodulcosigenin attenuates bleomycin‐induced pulmonary fibrosis via inhibiting AMPK‐mediated mesenchymal epithelial transition and oxidative stress

• Published in: Phytotherapy research 2022-10, Vol.36 (10), p.3911-3923
• Main Authors: Ding, Yue, Wang, Lei, Liu, Bei, Ren, Guoqing, Okubo, Ryosuke, Yu, Jing, Zhang, Chaofeng
• Format: Article
• Language: English
• Subjects: Alveoli; AMPK activation; Bleomycin; bryodulcosigenin; Collagen; epithelial–mesenchymal transition; Fibrosis; Histopathology; Inflammation; Lung diseases; Mesenchyme; Molecular docking; NOX4 protein; Oxidative stress; Pulmonary fibrosis; SIRT1 protein; Smad2 protein
• ISSN: 0951-418X; 1099-1573
• DOI: 10.1002/ptr.7535

Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in several organs, including the lungs. Bryodulcosigenin (BDG) is a cucurbitane‐type triterpene isolated from Siratia grosvenori and has clear‐cut anti‐inflammatory effects, yet its benefit of pulmonary fibrosis (PF) remains unclear. In this study, we investigated the protective effects of BDG (10 mg/kg/day, for 14 days) against TGF‐β1‐stimulated mouse alveolar epithelial MLE‐12 cells and bleomycin (BLM)‐induced PF mice. In vitro experiments showed that BDG could inhibit epithelial‐mesenchymal transition (EMT) and oxidative stress. In vivo experiments indicated that BDG could ameliorate BLM‐induced PF in mice as evidenced by characteristic structural changes in histopathology, increased collagen deposition and reduced survival and weight of mice. The abnormal increased expressions of TGF‐β1, p‐Smad2/3, α‐SMA, COL‐I, and NOX4 and decreased expressions for Sirt1 and p‐AMPK were improved in BDG treatment. But these beneficial effects could be eliminated by co‐treatment with Compound C (CC, a selective AMPK inhibitor). Molecular docking technology also revealed the potential of BDG to activate AMPK. In summary, AMPK activation modulated by BDG not only ameliorated TGF‐β1/Smad2/3 signaling pathways but also partially mediated the suppression effects on EMT and oxidative stress, thus mediating the anti‐fibrotic effects.