PT - JOURNAL ARTICLE AU - Yusuke Kurita AU - Jun Araya AU - Hiromiti Hara AU - Shunsuke Minagawa AU - Nayuta Saito AU - Nahoko Sato AU - Kazuya Tubouchi AU - Masahiro Yoshida AU - Kenji Kobayashi AU - Takanori Numata AU - Yumi Kaneko AU - Katutoshi Nakayama AU - Kazuyoshi Kuwano TI - Pirfenidone attenuates myofibroblast differentiation during insufficient mitophagy AID - 10.1183/13993003.congress-2016.OA482 DP - 2016 Sep 01 TA - European Respiratory Journal PG - OA482 VI - 48 IP - suppl 60 4099 - http://erj.ersjournals.com/content/48/suppl_60/OA482.short 4100 - http://erj.ersjournals.com/content/48/suppl_60/OA482.full SO - Eur Respir J2016 Sep 01; 48 AB - RATIONALE: Pirfenidone (PFD), is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis (IPF), but its precise mechanism of action remains to be determined. Accumulation of profibrotic myofibroblasts is a crucial process for fibrotic remodeling in IPF. We have demonstrated that insufficient mitophagy caused by reduced PARK2 expression may be involved in myofibroblast differentiation during IPF pathogenesis through ROS-mediated PDGF receptor (PDGFR) activation. In this study, we investigated the regulatory role of PFD in myofibroblast differentiation during insufficient mitophagy in lung fibroblasts (LF) and also during bleomycin (BLM)-induced lung fibrosis in the PARK2 KO mouse.METHODS: LF were isolated from human lung, and the effect of PFD on myofibroblast differentiation was evaluated by measuring expression of αSMA and type1 collagen. PDGFR activation was evaluated bydetecting phosphorylated forms. MitoSOX Red staining and DCFDA were used to evaluate mitochondrial ROS and intracellular ROS, respectively.Mice were given intratracheal injections of bleomycin (BLM) and intraesophageal administration of PFD.RESULTS: PFD inhibited PARK2 knockdown-induced myofibroblast differentiation by reducing mitochondrial ROS and PDGFR-PI3K-Akt activation in LF. BLM-treated PARK2 KO mice demonstrated augmentation of lung fibrosis development compared to BLM-treated C57BL/6 mice, which was efficiently attenuated by the administraion of PFD.CONCLUSION: PFD efficiently inhibits myofibroblast differentiation and development of BLM-induced lung fibrosis in the setting of insufficient mitophagy, which may at least partly explain the anti-fibrotic mechanisms of PFD for IPF treatment.