Effect of endothelial responses on sepsis-associated organ dysfunction

Abstract

Sepsis-related organ dysfunction is associated with increased morbidity and mortality. Previous studies have found that the endothelium plays crucial roles in maintaining the vascular permeability during sepsis, as well as in regulating inflammation and thrombosis. During sepsis, endothelial cells may release cytokines, chemokines, and pro-coagulant factors, as well as express adhesion molecules. In general, endothelial responses during sepsis typically inhibit bacterial transmission and coordinate leukocyte recruitment to promote bacterial clearance. However, excessive or prolonged endothelial activation can lead to impaired microcirculation, tissue hypoperfusion, and organ dysfunction. Given the structural and functional heterogeneity of endothelial cells in different organs, there are potential differences in endothelial responses by organ type, and the risk of organ damage may vary accordingly. This article reviews the endothelial response observed in sepsis and its effects on organ function, summarizes current progress in the development of therapeutic interventions targeting the endothelial response, and discusses future research directions to serve as a reference for researchers in the field.

Figure 1

An overview of endothelial responses to sepsis. ① During sepsis, various inflammatory factors activate ECs, leading to the activation of intracellular signal transduction. This activates transcription factors, increasing the transcription of proinflammatory cytokines, chemokines, adhesion molecules, and procoagulant factors. ② During sepsis, oxidative stress leads to dysregulation of NO synthase activity, resulting in excessive production of NO. Concurrently, sepsis induces ECs to produce ROS, which further damage them. ③ Sepsis causes disruption of intercellular connections between ECs, leading to increased endothelial permeability. ④ During sepsis, endothelial glycocalyx damage leads to increased inflammation, thrombosis, and hyperosmolarity. ⑤ Sepsis triggers EC activation, leading to increased surface expression of E-selectin, P-selectin, VCAM-1, and ICAM-1; followed by leukocyte rolling, adhesion, and migration on ECs. ⑥ Activated ECs express surface molecules such as vWF and P-selectin, mediating the formation of platelet–leukocyte aggregates and thereby promoting thrombus formation. ⑦ Damaged ECs can increase their release of vasoconstrictor factors and decrease their release of vasodilator factors. Vascular leakage and tissue edema can affect the local vascular tone. In addition, thrombosis and microcirculatory disturbances both alter vascular tone. NF-κB : Nuclear factor kappa B; ECs: Endothelial cells; eNOS: Endothelial nitric oxide synthase; E-Selectin: Endothelial selectin; ICAM-1: Intercellular adhesion molecule-1; IL-1: Interleukin-1; iNOS: Inducible nitric oxide synthase; NO: Nitric oxide; P-Selectin: Platelet selectin; ROS: Reactive oxygen species; TNF-α: Tumor necrosis factor-α; VCAM-1: Vascular cell adhesion molecule-1; vWF: von Willebrand factor.