Phosphodiesterase type 10A inhibitor attenuates lung fibrosis by targeting myofibroblast activation
Ya-Jun Li,
Jian-Rong Shi,
Shu-Chan Li,
Lu-Ming Wang,
Rana Dhar,
Ning Li,
Xin-Wei Cao,
Zi-Gang Li,
Hui-Fang Tang
Affiliations
Ya-Jun Li
Department of Pharmacology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
Jian-Rong Shi
Department of Clinical Laboratory, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310003, China
Shu-Chan Li
Department of Pharmacology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
Lu-Ming Wang
Department of Thoracic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China
Rana Dhar
Department of Pharmacology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
Ning Li
Department of Pharmacology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
Xin-Wei Cao
Department of Pharmacology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
Zi-Gang Li
Department of Anesthesiology, Women’s Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310006, China
Hui-Fang Tang
Department of Pharmacology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Clinical Laboratory, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, and Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Hangzhou, Zhejiang 310016, China; Corresponding author
Summary: 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.
