Li Ya-Jun, Shi Jian-Rong, Li Shu-Chan, Wang Lu-Ming, Dhar Rana, Li Ning, Cao Xin-Wei, Li Zi-Gang, Tang Hui-Fang
Department of Pharmacology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Department of Clinical Laboratory, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310003, China.
iScience. 2023 Apr 6;26(5):106586. doi: 10.1016/j.isci.2023.106586. eCollection 2023 May 19.
Pulmonary fibrosis (PF) is a fatal and irreversible respiratory disease accompanied by excessive fibroblast activation. Previous studies have suggested that cAMP signaling pathway and cGMP-PKG signaling pathway are continuously down-regulated in lung fibrosis, whereas PDE10A has a specifically expression in fibroblasts/myofibroblasts in lung fibrosis. In this study, we demonstrated that overexpression of PDE10A induces myofibroblast differentiation, and papaverine, as a PDE10A inhibitor used for vasodilation, inhibits myofibroblast differentiation in human fibroblasts, Meanwhile, papaverine alleviated bleomycin-induced pulmonary fibrosis and amiodarone-induced oxidative stress, papaverine downregulated VASP/β-catenin pathway to reduce the myofibroblast differentiation. Our results first demonstrated that papaverine inhibits TGFβ1-induced myofibroblast differentiation and lung fibrosis by VASP/β-catenin pathway.
肺纤维化（PF）是一种致命且不可逆的呼吸系统疾病，伴有成纤维细胞过度活化。先前的研究表明，环磷酸腺苷（cAMP）信号通路和环磷酸鸟苷-蛋白激酶G（cGMP-PKG）信号通路在肺纤维化中持续下调，而磷酸二酯酶10A（PDE10A）在肺纤维化的成纤维细胞/肌成纤维细胞中特异性表达。在本研究中，我们证明PDE10A的过表达诱导肌成纤维细胞分化，而用于血管舒张的PDE10A抑制剂罂粟碱可抑制人成纤维细胞中的肌成纤维细胞分化。同时，罂粟碱减轻了博来霉素诱导的肺纤维化和胺碘酮诱导的氧化应激，罂粟碱下调了血管舒张刺激磷蛋白（VASP）/β-连环蛋白通路以减少肌成纤维细胞分化。我们的结果首次证明，罂粟碱通过VASP/β-连环蛋白通路抑制转化生长因子β1（TGFβ1）诱导的肌成纤维细胞分化和肺纤维化。
