Sepsis: Unlocking the Endothelial Toolkit for Next-generation Therapeutics through Pharmacologist’s Lens

Abstract Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, leading to organ dysfunction. Endothelial dysfunction is recognized as a central event in the pathophysiology of sepsis and septic shock, preceding and driving multiple organ dysfunction and high mortality rates. Lipopolysaccharide and inflammatory cytokines (e.g., tumor necrosis factor alpha, interleukin IL-1 β, IL-6) activate endothelial cells (ECs), resulting in the loss of tight junction integrity, increased vascular permeability, and leading to interstitial edema. Activated ECs express adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin) that facilitate leukocyte recruitment and extravasation, further amplifying inflammation. In parallel, the balance between pro- and anticoagulant pathways is disrupted, with upregulation of tissue factor and downregulation of thrombomodulin and the protein C pathway, promoting microvascular thrombosis. On the other hand, nitric oxide dysregulation contributes to vasoplegia, hypotension, and altered microcirculatory flow. Moreover, shedding and degradation of the endothelial glycocalyx further enhance vascular leak, interstitial edema, leukocyte adhesion, and subsequent tissue hypoperfusion. This widespread endothelial injury is the nexus linking systemic inflammation to critical organ damage, including acute lung and kidney injury as well as disseminated intravascular coagulation. Circulating biomarkers of endothelial activation and glycocalyx shedding, such as angiopoietin-2, soluble thrombomodulin, and syndecan-1, have emerged as potential diagnostic and prognostic tools. In conclusion, endothelial dysfunction is not merely a consequence but a critical driver of sepsis pathophysiology. Targeting endothelial stabilization by modulating inflammation, preserving the glycocalyx, and restoring vascular homeostasis represents a promising therapeutic strategy to mitigate organ failure and improve outcomes in sepsis.