Involvement of GPx4-regulated lipid peroxidation in idiopathic pulmonary fibrosis pathogenesis

Kazuya Tsubouchi, Jun Araya, Masahiro Yoshida, Taro Sakamoto, Tomoko Koumura, Shunsuke Minagawa, Hiromichi Hara, Yusuke Hosaka, Akihiro Ichikawa, Nayuta Saito, Tsukasa Kadota, Yusuke Kurita, Kenji Kobayashi, Saburo Ito, Yu Fujita, Hirofumi Utsumi, Mitsuo Hashimoto, Hiroshi Wakui, Takanori Numata, Yumi KanekoShohei Mori, Hisatoshi Asano, Hideki Matsudaira, Takashi Ohtsuka, Katsutoshi Nakayama, Yoichi Nakanishi, Hirotaka Imai, Kazuyoshi Kuwano

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

The imbalanced redox status in lung has been widely implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis. To regulate redox status, hydrogen peroxide must be adequately reduced to water by glutathione peroxidases (GPx). Among GPx isoforms, GPx4 is a unique antioxidant enzyme that can directly reduce phospholipid hydroperoxide. Increased lipid peroxidation products have been demonstrated in IPF lungs, suggesting the participation of imbalanced lipid peroxidation in IPF pathogenesis, which can be modulated by GPx4. In this study, we sought to examine the involvement of GPx4-modulated lipid peroxidation in regulating TGF-β-induced myofibroblast differentiation. Bleomycin-induced lung fibrosis development in mouse models with genetic manipulation of GPx4 were examined. Immunohistochemical evaluations for GPx4 and lipid peroxidation were performed in IPF lung tissues. Immunohistochemical evaluations showed reduced GPx4 expression levels accompanied by increased 4-hydroxy-2-nonenal in fibroblastic focus in IPF lungs. TGF-β-induced myofibroblast differentiation was enhanced by GPx4 knockdown with concomitantly enhanced lipid peroxidation and SMAD2/SMAD3 signaling. Heterozygous GPx4-deficient mice showed enhancement of bleomycin-induced lung fibrosis, which was attenuated in GPx4-transgenic mice in association with lipid peroxidation and SMAD signaling. Regulating lipid peroxidation by Trolox showed efficient attenuation of bleomycin-induced lung fibrosis development. These findings suggest that increased lipid peroxidation resulting from reduced GPx4 expression levels may be causally associated with lung fibrosis development through enhanced TGF-β signaling linked to myofibroblast accumulation of fibroblastic focus formation during IPF pathogenesis. It is likely that regulating lipid peroxidation caused by reduced GPx4 can be a promising target for an antifibrotic modality of treatment for IPF.

Original languageEnglish
Pages (from-to)2076-2087
Number of pages12
JournalJournal of Immunology
Volume203
Issue number8
DOIs
Publication statusPublished - Oct 15 2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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