Neutrophils Extracellular Traps Impair Lung Endothelial Proliferation in Sepsis via PLK1 Inhibition and Cell Cycle Arrest.

Purpose: Sepsis continues to pose a significant threat to global health, characterized by elevated mortality rates. Pulmonary complications frequently develop in septic patients, with endothelial dysfunction correlating with adverse clinical outcomes. While overproduction of neutrophil extracellular traps (NETs) is implicated in vascular damage, their specific influence on the regenerative potential of pulmonary endothelial cells requires further elucidation. Our investigation aims to address this critical knowledge gap. Patients and Methods: Clinical samples from sepsis patients and healthy controls were analyzed to establish the correlation between NETs and pulmonary endothelial injury. An in vivo sepsis model was generated through cecal ligation and puncture (CLP) in mice, with sham surgery animals serving as reference group. Human umbilical vein endothelial cells (HUVECs) were employed for in vitro assessment of NETs-mediated cell cycle modulation. Results: Elevated NETs formation was observed in septic patients, showing positive association with inflammatory damage. CLP-induced mice demonstrated substantially increased NETs levels, pronounced pulmonary vascular permeability, and notable endothelial cell depletion. DNase I-mediated NETs degradation alleviated pulmonary inflammation and promoted endothelial recovery. Both experimental models revealed that excessive NETs release during sepsis compromises endothelial proliferation via polo-like kinase 1 (PLK1) pathway inhibition and subsequent G2/M phase arrest. Conclusion: This study establishes that NETs accumulation in septic pulmonary injury hinders endothelial regeneration and vascular repair through PLK1 signaling suppression and G2/M cell cycle blockade.