Potential role of ferroptosis in sterile acute lung injury induced by a non-hypoxic ischemia-reperfusion insult

Objective(s): Ferroptosis, a regulated form of necrotic cell death, is implicated in the pathogenesis of hypoxic lung ischemia-reperfusion injury (LIRI). However, its role in non-hypoxic LIRI, which occurs in common clinical conditions such as trauma and pulmonary embolism, remains unclear. Given that ferroptosis has been implicated in sterile inflammation and lipid peroxidation is a hallmark of this process, this study aimed to investigate the potential role of ferroptosis in inflammatory responses during non-hypoxic LIRI.Materials and Methods: Non-hypoxic LIRI was induced in C۵۷BL/۶ mice by occluding the left pulmonary artery for ۱ hr, followed by ۳۰ min of reperfusion. The treatment group received liproxstatin-۱ (Lip-۱; ۱۰ mg/kg, IP) ۱ hr before surgery. IL-۶ levels in plasma and lung tissue were measured by ELISA. For the in vitro model, normal human bronchial epithelial (NHBE) cells were exposed to nutritional ischemia for ۱ hr and then reperfused for ۲ hr. Cells were pretreated with Lip-۱ (۲۰۰ nM) ۱۲ hr before ischemia. CXCL۱ release was measured by ELISA, and lipid reactive oxygen species (ROS) accumulation was assessed by BODIPY ۵۸۱/۵۹۱ C۱۱ fluorescence.Results: Non-hypoxic LIRI markedly increased IL-۶ levels in plasma and lung tissue, as well as CXCL۱ levels and lipid ROS accumulation in NHBE cells. Pretreatment with Lip-۱ significantly reduced these inflammatory responses and lipid ROS accumulation compared with untreated LIRI.Conclusion: Our findings suggest that ferroptosis-associated lipid peroxidation is associated with sterile inflammatory responses during non-hypoxic LIRI in both systemic and epithelial compartments. Lip-۱ attenuated these responses, highlighting a potential strategy for non-hypoxic LIRI.

کلیدواژه ها:

Chemokine CXCL۱ ، Inflammation ، Interleukin-۶ ، Lipid Peroxidation ، Reperfusion injury