Fig. 4: The pathophysiologic process of ECs PCD in sepsis.

During sepsis, PAMPs and DAMPs activate programmed cell death pathways in endothelial cells, triggering endoplasmic reticulum stress, increased nuclear translocation and translation, peroxisome accumulation, enhanced autophagic lysosomal activity, and mitochondrial dysfunction with subsequent release of reactive oxygen species (ROS) and mitochondrial DNA (mtDNA). These components further act as DAMPs, amplifying PCD-related signaling cascades. Endothelial cell death leads to structural and functional vascular impairment, characterized by: a. degradation of the endothelial glycocalyx and reduced glycocalyx thickness; b. enhanced leukocyte adhesion and transmigration; c. coagulopathy and thrombus formation; d. focal inflammation and its systemic dissemination. At the tissue level, these alterations manifest as hemodynamic instability and impaired microcirculatory perfusion. Multi-organ involvement results in acute clinical manifestations of injury, potentially progressing to disseminated intravascular coagulation (DIC), systemic inflammatory response syndrome (SIRS), and multiple organ dysfunction syndrome (MODS). In critical cases, these pathological changes culminate in fatal outcomes.