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

doi:10.1016/j.isci.2023.106586

Phosphodiesterase type 10A inhibitor attenuates lung fibrosis by targeting myofibroblast activation

iScience. 2023 Apr 6;26(5):106586. doi: 10.1016/j.isci.2023.106586. eCollection 2023 May 19.

Authors

Ya-Jun Li¹, Jian-Rong Shi², Shu-Chan Li¹, Lu-Ming Wang³, Rana Dhar¹, Ning Li¹, Xin-Wei Cao¹, Zi-Gang Li⁴, Hui-Fang Tang^{1

5}

Affiliations

¹ Department of Pharmacology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
² Department of Clinical Laboratory, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310003, China.
³ Department of Thoracic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China.
⁴ Department of Anesthesiology, Women's Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang 310006, China.
⁵ 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.

Abstract

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.

Keywords: Molecular biology; Pharmacology.