Respiratory Research (Jun 2017)

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 Numata,
  • Yumi Kaneko,
  • Hisatoshi Asano,
  • Makoto Yamashita,
  • Makoto Odaka,
  • Toshiaki Morikawa,
  • Katsutoshi Nakayama,
  • Kazuyoshi Kuwano

DOI
https://doi.org/10.1186/s12931-017-0600-3
Journal volume & issue
Vol. 18, no. 1
pp. 1 – 14

Abstract

Read online

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.

Keywords