Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy

Respiratory Research

Research

Makoto Yamashita¹  Makoto Odaka¹  Hisatoshi Asano¹  Toshiaki Morikawa¹  Yumi Kaneko²  Nayuta Saito²  Haruhiko Yanagisawa²  Takanori Numata²  Hirofumi Utsumi²  Takeo Ishikawa²  Kenji Kobayashi²  Shunsuke Minagawa²  Kazuyoshi Kuwano²  Yu Fujita²  Jun Araya²  Katsutoshi Nakayama²  Hiroshi Wakui²  Hiromichi Hara²  Yusuke Kurita²  Masahiro Yoshida²  Yutaka Yoshii²  Saburo Ito²  Akihiro Ichikawa²  Tsukasa Kadota²  Mitsuo Hashimoto²  Nahoko Sato³  Kazuya Tsubouchi⁴ 

[1] Division of Chest Diseases; Department of Surgery, Jikei University School of Medicine, Tokyo, Japan;Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, 105-8461, Tokyo, Japan;Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, 105-8461, Tokyo, Japan;Department of Respiratory Medicine, Faculty of Life Science, Kumamoto University, Kumamoto, Japan;Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, 105-8461, Tokyo, Japan;Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;

关键词: Autophagy;    IPF;    Myofibroblast;    Mitophagy;    Pirfenidone;   

DOI  :  10.1186/s12931-017-0600-3

 received in 2017-02-16, accepted in 2017-05-26,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundPirfenidone (PFD) is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis (IPF), but its precise mechanism of action remains elusive. Accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodeling in IPF. Recent findings show participation of autophagy/mitophagy, part of the lysosomal degradation machinery, in IPF pathogenesis. Mitophagy has been implicated in myofibroblast differentiation through regulating mitochondrial reactive oxygen species (ROS)-mediated platelet-derived growth factor receptor (PDGFR) activation. In this study, the effect of PFD on autophagy/mitophagy activation in lung fibroblasts (LF) was evaluated, specifically the anti-fibrotic property of PFD for modulation of myofibroblast differentiation during insufficient mitophagy.MethodsTransforming growth factor-β (TGF-β)-induced or ATG5, ATG7, and PARK2 knockdown-mediated myofibroblast differentiation in LF were used for in vitro models. The anti-fibrotic role of PFD was examined in a bleomycin (BLM)-induced lung fibrosis model using PARK2 knockout (KO) mice.ResultsWe found that PFD induced autophagy/mitophagy activation via enhanced PARK2 expression, which was partly involved in the inhibition of myofibroblast differentiation in the presence of TGF-β. PFD inhibited the myofibroblast differentiation induced by PARK2 knockdown by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation. BLM-treated PARK2 KO mice demonstrated augmentation of lung fibrosis and oxidative modifications compared to those of BLM-treated wild type mice, which were efficiently attenuated by PFD.ConclusionsThese results suggest that PFD induces PARK2-mediated mitophagy and also inhibits lung fibrosis development in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for IPF treatment.

【 授权许可】

CC BY   
© The Author(s). 2017