Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis

Masahiro Yoshida, Shunsuke Minagawa (), Jun Araya, Taro Sakamoto, Hiromichi Hara, Kazuya Tsubouchi, Yusuke Hosaka, Akihiro Ichikawa, Nayuta Saito, Tsukasa Kadota, Nahoko Sato, Yusuke Kurita, Kenji Kobayashi, Saburo Ito, Hirohumi Utsumi, Hiroshi Wakui, Takanori Numata, Yumi Kaneko, Shohei Mori, Hisatoshi Asano, Makoto Yamashita, Makoto Odaka, Toshiaki Morikawa, Katsutoshi Nakayama, Takeo Iwamoto, Hirotaka Imai and Kazuyoshi Kuwano
Additional contact information
Masahiro Yoshida: Jikei University School of Medicine
Shunsuke Minagawa: Jikei University School of Medicine
Jun Araya: Jikei University School of Medicine
Taro Sakamoto: Kitasato University
Hiromichi Hara: Jikei University School of Medicine
Kazuya Tsubouchi: Jikei University School of Medicine
Yusuke Hosaka: Jikei University School of Medicine
Akihiro Ichikawa: Jikei University School of Medicine
Nayuta Saito: Jikei University School of Medicine
Tsukasa Kadota: Jikei University School of Medicine
Nahoko Sato: Jikei University School of Medicine
Yusuke Kurita: Jikei University School of Medicine
Kenji Kobayashi: Jikei University School of Medicine
Saburo Ito: Jikei University School of Medicine
Hirohumi Utsumi: Jikei University School of Medicine
Hiroshi Wakui: Jikei University School of Medicine
Takanori Numata: Jikei University School of Medicine
Yumi Kaneko: Jikei University School of Medicine
Shohei Mori: Jikei University School of Medicine
Hisatoshi Asano: Jikei University School of Medicine
Makoto Yamashita: Jikei University School of Medicine
Makoto Odaka: Jikei University School of Medicine
Toshiaki Morikawa: Jikei University School of Medicine
Katsutoshi Nakayama: Jikei University School of Medicine
Takeo Iwamoto: Jikei University School of Medicine
Hirotaka Imai: Kitasato University
Kazuyoshi Kuwano: Jikei University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Ferroptosis is a necrotic form of regulated cell death (RCD) mediated by phospholipid peroxidation in association with free iron-mediated Fenton reactions. Disrupted iron homeostasis resulting in excessive oxidative stress has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we demonstrate the involvement of ferroptosis in COPD pathogenesis. Our in vivo and in vitro models show labile iron accumulation and enhanced lipid peroxidation with concomitant non-apoptotic cell death during cigarette smoke (CS) exposure, which are negatively regulated by GPx4 activity. Treatment with deferoxamine and ferrostatin-1, in addition to GPx4 knockdown, illuminate the role of ferroptosis in CS-treated lung epithelial cells. NCOA4-mediated ferritin selective autophagy (ferritinophagy) is initiated during ferritin degradation in response to CS treatment. CS exposure models, using both GPx4-deficient and overexpressing mice, clarify the pivotal role of GPx4-regulated cell death during COPD. These findings support a role for cigarette smoke-induced ferroptosis in the pathogenesis of COPD.

Date: 2019
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DOI: 10.1038/s41467-019-10991-7

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