Long-Term Cigarette Smoke Exposure Promotes Neutrophil Ferroptosis Resistance Inducing Net Formation and Driving Glucocorticoid Resistance in Copd

BackgroundGlucocorticoid resistance increases the frequency of acute exacerbations and the risk of death in chronic obstructive pulmonary disease (COPD) patients with a history of long-term heavy somking.ObjectiveThis study aimed to investigate the role of neutrophil ferroptosis resistance and the formation of neutrophil extracellular traps (NETs) in cigarette smoke (CS)-induced glucocorticoid resistance in COPD.MethodsClinical specimens were collected from COPD patients and healthy subjects. A mouse model of COPD induced by CS exposure was established in vivo. Neutrophils were isolated from the peripheral blood of human donors and exposed to cigarette smoke extract (CSE) in vitro.ResultsExtensive NET formation was observed in COPD patients with a history of long-term heavy-smoking and was closely related to glucocorticoid resistance. In vivo, we found that prolonged CS exposure promoted NET formation and that rendered dexamethasone (Dex) treatment was ineffective at alleviating lung inflammation in COPD model mice. However, the the NET-degrading agent deoxyribonuclease I (DNase I) could increase sensitivity to Dex in COPD model mice. In vitro experiments demonstrated that CSE increased neutrophil cell viability by activating the Nrf2/SLC7A11/GPX4 pathway and inducing ferroptosis resistance in neutrophils. We found that neutrophil-specific GPX4 knockout inhibited CS-induced NET formation, increased sensitivity to Dex, and alleviated CS-induced glucocorticoid resistance in vivo and in vitro.ConclusionCS promotes glucocorticoid resistance in COPD by inducing ferroptosis resistance in neutrophils and further resulting in NET formation.