LXA4 alleviates inflammation and ferroptosis in cigarette smoke induced chronic obstructive pulmonary disease via the ALX/FPR2 receptor

Ferroptosis, a form of regulated cell death, is closely related to the development of chronic obstructive pulmonary disease (COPD). Lipoxin A4 (LXA4) has garnered attention due to its well-established anti-inflammatory and antioxidant properties. However, whether its role in COPD is associated with the inhibition of Ferroptosis is unknown. In this study, we employed a mouse model of COPD that was subjected to cigarette smoke (CS) exposure, alongside a cigarette smoke extract (CSE) stimulated murine alveolar macrophage (MH-S) model, to investigate the role and underlying molecular mechanisms of LXA4 in the context of COPD. Our results indicated that LXA4 intervention reversed the reduction in pulmonary function, emphysema, and airway inflammation in COPD mice. Moreover, LXA4 decreased the markers of lipid peroxidation and Ferroptosis in pulmonary tissues challenged with CS. The effects of LXA4 were also observed in CSE stimulated MH-S cells. Mechanistically, LXA4 was found to upregulate the expression of formyl peptide receptor 2 (ALX/FPR2), while simultaneously downregulating the phosphorylation of p38 MAPK, both in vivo and in vitro. Furthermore, the p38 MAPK Inhibitor SB203580 reversed CSE-induced inflammation and Ferroptosis, and the protective effect of LXA4 was offset by treatment with the ALX/FPR2 antagonist WRW4. Collectively, LXA4 suppresses the p38 MAPK pathway to inhibit inflammation and Ferroptosis induced by CS via the ALX/FPR2 receptor, indicating that LXA4 could be a promising candidate for COPD.

Alveolar macrophages; Chronic obstructive pulmonary disease; Cigarette smoke; Ferroptosis; Lipoxin A4.