NETs induce ferroptosis of endothelial cells in LPS-ALI through SDC-1/HS and downstream pathways

BACKGROUND: Extracellular neutrophil extracellular traps (NETs) play an important role in acute lung injury (ALI), but their mechanisms are still unclear. The aim of this study is to explore the effects of NETs on endothelial glycocalyx/HGF/cMET pathway and ferroptosis in ALI and elucidate their potential mechanisms. METHODS: Plasma was collected from healthy and sepsis patients to test for differences in neutrophil elastase (NE) expression of NETs components. In addition, LPS-ALI mice and endothelial cell injury models were established, and NETs were disrupted by siPAD4 (a driver gene for NETs) and sivelestat (an inhibitor of the NETs component) in the mice and by sivelestat in the endothelial cell injury models, and the effects of NETs on the SDC-1/HS/HGF/cMET pathway were studied. To verify the relationship between NETs and ferroptosis, Fer1, a ferroptosis inhibitor, was added as a positive control to observe the effect of NETs on ferroptosis indicators. RESULTS: The expression level of NE was significantly higher in the plasma of sepsis patients. In ALI mice, intervention in the generation of NETs reduced pulmonary vascular permeability, protected the integrity of SDC-1/HS and promoted the downstream HGF/cMET pathway. In addition, sivelestat also improved the survival rate of mice, decreased the serious degree of ferroptosis. In the endothelial cells, the results were consistent with those of the ALI mice. CONCLUSION: The study indicates that inhibiting the production of NETs can protect the normal conduction of the SDC-1/HS/HGF/cMET signalling pathway and reduce the severity of ferroptosis.