Research advances on the role of programmed endothelial cell death in sepsis.

Abstract

Sepsis is a life-threatening systemic inflammatory response syndrome triggered by infection, characterized by a dysregulated host immune response to pathogenic organisms and associated with substantial morbidity and mortality. According to the most recent sepsis guidelines, effective monitoring and therapeutic strategies remain insufficient, leading to suboptimal patient outcomes. Endothelial cells (ECs) constitute a critical pathophysiological nexus in sepsis pathogenesis, wherein their dysregulation disrupts both microvascular homeostasis and endothelial barrier competence. During sepsis, aberrant activation of programmed cell death (PCD) pathways in ECs induces both structural and functional disruptions, thereby enhancing vascular permeability, causing hemodynamic instability, promoting systemic circulatory dysfunction, and compromising tissue perfusion. These pathophysiological derangements potentiate a vicious cycle of systemic inflammatory amplification, exacerbate disseminated intravascular coagulation, and culminate in lethal multiple organ dysfunction syndrome. This comprehensive review systematically evaluates contemporary insights into the molecular pathophysiology of PCD pathways in endothelial cells during sepsis, with particular emphasis on their mechanistic interplay and therapeutic implications, providing an in-depth understanding of their contributions to sepsis pathophysiology. Additionally, we explore the potential of key PCD-associated molecules as biomarkers for monitoring and evaluating vascular function and permeability in septic patients. Finally, we discuss the current state of drug development targeting ECs' PCD and their prospective therapeutic implications for sepsis, offering valuable insights for future basic research and clinical applications.