Ferroptosis-associated processes are linked to airway inflammation in a mouse model of cigarette smoke-exacerbated asthma

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Background Cigarette smoke (CS) exacerbates airway inflammation in asthma. However, the mechanisms by which CS exacerbates pre-existing allergic airway inflammation remain incompletely understood. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has been implicated in several CS-associated pulmonary disorders. This study investigated whether ferroptosis-associated processes are involved in CS-exacerbated allergic airway inflammation. Methods A smoke-exacerbated asthma-like mouse model was established by exposing papain-exposed male mice to CS (n = 4 mice per group). Ferroptosis-associated alterations were assessed using Prussian blue staining, Gpx4 and Ncoa4 messenger RNA (mRNA) expression, the reduced glutathione/oxidized glutathione ratio, and malondialdehyde levels. Airway inflammation was evaluated using histological analysis, bronchoalveolar lavage fluid cell counts, and inflammatory mediator measurements. These processes were further examined pharmacologically using erastin and liproxstatin-1 (Lip-1). Data were analyzed using two-way or one-way analysis of variance, the Kruskal–Wallis test, or unpaired two-tailed Student's t-tests, with appropriate multiple-comparisons tests where applicable. Results CS exposure was associated with focal Prussian blue-detectable ferric iron deposition, altered lipid-redox status, and changes in ferroptosis-associated mRNA expression, with several alterations more pronounced in papain-exposed mice. Erastin was associated with more prominent focal ferric iron deposition and increased several inflammatory responses in papain-exposed mice. In contrast, Lip-1 was associated with less prominent focal ferric iron deposition, reduced malondialdehyde levels, and attenuated several inflammatory responses in the smoke-exacerbated asthma-like model. Conclusions CS exposure was associated with ferroptosis-associated iron and lipid-redox alterations in the lung, and pharmacological modulation of these processes altered the severity of pre-existing allergic airway inflammation. These findings support an association between ferroptosis-associated processes and smoke-exacerbated allergic airway inflammation and warrant further mechanistic and translational investigation.