The emerging role of mtDNA release in sepsis: Current evidence and potential therapeutic targets.

Sepsis is a systemic inflammatory reaction caused by infection, and severe sepsis can develop into septic shock, eventually leading to multiorgan dysfunction and even death. In recent years, studies have shown that mitochondrial damage is closely related to the occurrence and development of sepsis. Recent years have seen a surge in concern over mitochondrial DNA (mtDNA), as anomalies in this material can lead to cellular dysfunction, disruption of aerobic respiration, and even death of the cell. In this review, we discuss the latest findings on the mechanisms of mitochondrial damage and the molecular mechanisms controlling mitochondrial mtDNA release. We also explored the connection between mtDNA misplacement and inflammatory activation. Additionally, we propose potential therapeutic targets of mtDNA for sepsis treatment.

Neutrophil Extracellular Traps Upregulate p21 and Suppress Cell Cycle Progression to Impair Endothelial Regeneration after Inflammatory Lung Injury.

Background: Sepsis is a major cause of ICU admissions, with high mortality and morbidity. The lungs are particularly vulnerable to infection and injury, and restoration of vascular endothelial homeostasis after injury is a crucial determinant of outcome. Neutrophil extracellular trap (NET) release strongly correlates with the severity of lung tissue damage. However, little is known about whether NETs affect endothelial cell (EC) regeneration and repair. Methods: Eight- to ten-week-old male C57BL/6 mice were injected intraperitoneally with a sublethal dose of LPS to induce acute lung inflammatory injury or with PBS as a control. Blood samples and lung tissues were collected to detect NET formation and lung endothelial cell proliferation. Human umbilical vein endothelial cells (HUVECs) were used to determine the role of NETs in cell cycle progression in vitro. Results: Increased NET formation and impaired endothelial cell proliferation were observed in mice with inflammatory lung injury following septic endotoxemia. Degradation of NETs with DNase I attenuated lung inflammation and facilitated endothelial regeneration. Mechanistically, NETs induced p21 upregulation and cell cycle stasis to impair endothelial repair. Conclusions: Our findings suggest that NET formation impairs endothelial regeneration and vascular repair through the induction of p21 and cell cycle arrest during inflammatory lung injury.