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Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy.
Respir Res. 2017 06 02; 18(1):114.RR

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.

Authors+Show Affiliations

Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan. md986001@yahoo.co.jp.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan. Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, 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, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.Division of Chest Diseases; Department of Surgery, Jikei University School of Medicine, Tokyo, Japan.Division of Chest Diseases; Department of Surgery, Jikei University School of Medicine, Tokyo, Japan.Division of Chest Diseases; Department of Surgery, Jikei University School of Medicine, Tokyo, Japan.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, Tokyo, 105-8461, Japan.Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28577568

Citation

Kurita, Yusuke, et al. "Pirfenidone Inhibits Myofibroblast Differentiation and Lung Fibrosis Development During Insufficient Mitophagy." Respiratory Research, vol. 18, no. 1, 2017, p. 114.
Kurita Y, Araya J, Minagawa S, et al. Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy. Respir Res. 2017;18(1):114.
Kurita, Y., Araya, J., Minagawa, S., Hara, H., Ichikawa, A., Saito, N., Kadota, T., Tsubouchi, K., Sato, N., Yoshida, M., Kobayashi, K., Ito, S., Fujita, Y., Utsumi, H., Yanagisawa, H., Hashimoto, M., Wakui, H., Yoshii, Y., Ishikawa, T., ... Kuwano, K. (2017). Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy. Respiratory Research, 18(1), 114. https://doi.org/10.1186/s12931-017-0600-3
Kurita Y, et al. Pirfenidone Inhibits Myofibroblast Differentiation and Lung Fibrosis Development During Insufficient Mitophagy. Respir Res. 2017 06 2;18(1):114. PubMed PMID: 28577568.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pirfenidone inhibits myofibroblast differentiation and lung fibrosis development during insufficient mitophagy. AU - Kurita,Yusuke, AU - Araya,Jun, AU - Minagawa,Shunsuke, AU - Hara,Hiromichi, AU - Ichikawa,Akihiro, AU - Saito,Nayuta, AU - Kadota,Tsukasa, AU - Tsubouchi,Kazuya, AU - Sato,Nahoko, AU - Yoshida,Masahiro, AU - Kobayashi,Kenji, AU - Ito,Saburo, AU - Fujita,Yu, AU - Utsumi,Hirofumi, AU - Yanagisawa,Haruhiko, AU - Hashimoto,Mitsuo, AU - Wakui,Hiroshi, AU - Yoshii,Yutaka, AU - Ishikawa,Takeo, AU - Numata,Takanori, AU - Kaneko,Yumi, AU - Asano,Hisatoshi, AU - Yamashita,Makoto, AU - Odaka,Makoto, AU - Morikawa,Toshiaki, AU - Nakayama,Katsutoshi, AU - Kuwano,Kazuyoshi, Y1 - 2017/06/02/ PY - 2017/02/16/received PY - 2017/05/26/accepted PY - 2017/6/5/entrez PY - 2017/6/5/pubmed PY - 2018/6/15/medline KW - Autophagy KW - IPF KW - Mitophagy KW - Myofibroblast KW - Pirfenidone SP - 114 EP - 114 JF - Respiratory research JO - Respir. Res. VL - 18 IS - 1 N2 - 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. SN - 1465-993X UR - https://www.unboundmedicine.com/medline/citation/28577568/Pirfenidone_inhibits_myofibroblast_differentiation_and_lung_fibrosis_development_during_insufficient_mitophagy_ L2 - https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-017-0600-3 DB - PRIME DP - Unbound Medicine ER -