Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy

Yusuke Kurita, Jun Araya, Shunsuke Minagawa, Hiromichi Hara, Akihiro Ichikawa, Nayuta Saito, Tsukasa Kadota, Kazuya Tsubouchi, Nahoko Sato, Masahiro Yoshida, Kenji Kobayashi, Saburo Ito, Yu Fujita, Hirofumi Utsumi, Haruhiko Yanagisawa, Mitsuo Hashimoto, Hiroshi Wakui, Yutaka Yoshii, Takeo Ishikawa, Takanori NumataYumi Kaneko, Hisatoshi Asano, Makoto Yamashita, Makoto Odaka, Toshiaki Morikawa, Katsutoshi Nakayama, Kazuyoshi Kuwano

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57 Citations (Scopus)

Abstract

Background: Pirfenidone (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. Methods: Transforming 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. Results: We 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. Conclusions: These 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.

Original languageEnglish
Article number114
JournalRespiratory Research
Volume18
Issue number1
DOIs
Publication statusPublished - Jun 2 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine

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