TY - JOUR
T1 - Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis
AU - Yoshida, Masahiro
AU - Minagawa, Shunsuke
AU - Araya, Jun
AU - Sakamoto, Taro
AU - Hara, Hiromichi
AU - Tsubouchi, Kazuya
AU - Hosaka, Yusuke
AU - Ichikawa, Akihiro
AU - Saito, Nayuta
AU - Kadota, Tsukasa
AU - Sato, Nahoko
AU - Kurita, Yusuke
AU - Kobayashi, Kenji
AU - Ito, Saburo
AU - Utsumi, Hirohumi
AU - Wakui, Hiroshi
AU - Numata, Takanori
AU - Kaneko, Yumi
AU - Mori, Shohei
AU - Asano, Hisatoshi
AU - Yamashita, Makoto
AU - Odaka, Makoto
AU - Morikawa, Toshiaki
AU - Nakayama, Katsutoshi
AU - Iwamoto, Takeo
AU - Imai, Hirotaka
AU - Kuwano, Kazuyoshi
N1 - Funding Information:
The authors thank Agilent Technologies Japan, Ltd for technical assistance with ICP-MS. We also thank Stephanie Cambier for comments on the manuscript. This work was supported in part by Grants-in-Aid from Scientific Research (C) (17K09673, 26460075) from JSPS KAKENHI, Scientific Research on Innovative Areas (16H01367 and 17H05513) from a MEXT (Ministry of Education, Culture, Sports, Science and Technology), Japan, GlaxoSmithKline research grant (2016), and AMED under Grant Number, JP18gm0910013.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-10991-7
DO - 10.1038/s41467-019-10991-7
M3 - Article
C2 - 31316058
AN - SCOPUS:85069450147
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3145
ER -