Long-Term Cigarette Smoke Exposure Promotes Neutrophil Ferroptosis Resistance, Inducing Neutrophil Extracellular Trap Formation and Driving Glucocorticoid Resistance in Chronic Obstructive Pulmonary Disease.

Glucocorticoid 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 smoking. In this study we 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. We collected clinical specimens 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 CS extract in vitro. We found extensive 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 ineffective at alleviating lung inflammation in COPD model mice. However, the NET degrading agent deoxyribonuclease I could increase sensitivity to Dex in COPD model mice. In vitro experiments demonstrated that CS extract increased neutrophil cell viability by activating the Nrf2/SLC7A11/GPX4 pathway and inducing ferroptosis resistance in neutrophils. And 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. In conclusion CS promotes glucocorticoid resistance in COPD by inducing ferroptosis resistance in neutrophils, further resulting in NET formation.