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Nat Commun. 2019 Jul 17;10(1):3145. doi: 10.1038/s41467-019-10991-7.

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

Author information

1
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 105-8461, Tokyo, Japan.
2
Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, 105-8461, Tokyo, Japan. shunske@jikei.ac.jp.
3
Laboratory of Hygienic Chemistry and Medicinal Research Laboratories, School of Pharmaceutical Sciences, Kitasato University, 108-8641, Tokyo, Japan.
4
Division of Chest Diseases, Department of Surgery, Jikei University School of Medicine, 105-8461, Tokyo, Japan.
5
Division of Molecular Cell Biology, Core Research Facilities for Basic Science, Jikei University School of Medicine, 105-8461, Tokyo, Japan.

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.

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