Bench-to-bedside review: endothelial cell dysfunction in severe sepsis: a role in organ dysfunction?

Abstract

During the past decade a unifying hypothesis has been developed to explain the vascular changes that occur in septic shock on the basis of the effect of inflammatory mediators on the vascular endothelium. The vascular endothelium plays a central role in the control of microvascular flow, and it has been proposed that widespread vascular endothelial activation, dysfunction and eventually injury occurs in septic shock, ultimately resulting in multiorgan failure. This has been characterized in various models of experimental septic shock. Now, direct and indirect evidence for endothelial cell alteration in humans during septic shock is emerging. The present review details recently published literature on this rapidly evolving topic.

Figure 1

Thrombomodulin and protein C activation at the microcirculatory level. The endothelial cell surface thrombin (Th)-binding protein thrombomodulin (TM) is responsible for inhibition of thrombin activity. TM, when bound to Th, forms a potent protein C activator complex. Loss of TM and/or internalization results in Th-thrombin receptor (TR) interaction. Loss of TM and associated protein C activation represents the key event of decreased endothelial coagulation modulation ability and increased inflammation pathways. Adapted from Iba and coworkers [88]. ATIII, antithrombin III; NF-κ, nuclear factor-κB; PAI, plasminogen activator inhibitor; Th, thrombin; TM, thrombomodulin.

Figure 2

Coagulation and fibrinolysis pathways. Unperturbed endothelial cells (ECs) provide anticoagulant (tissue factor pathway inhibitor [TFPI], protein C [PC], protein S [PS], thrombomodulin [TM], heparan sulphate [HS]) and fibrinolytic (tissue plasminogen activator [tPA]) properties. ATIII, antithrombin III; FXa, coagulation factor Xa; M, activated monocyte; PAI, plasminogen activator inhibitor; SMC, smooth muscle cell; TF, tissue factor.

Figure 3

Sepsis and coagulation-fibrinolysis pathways. Exposure to inflammatory and/or septic stimuli rapidly leads to procoagulant behaviour. The profibrinolytic property of endothelial cells (ECs) is blunted, due to decreased release of tissue plasminogen activator. This occurs in a context of increased plasminogen activator inhibitor (PAI)-1 release with antifibrinolysis. LPS, lipopolysaccharide; M, activated monocyte; SMC, smooth muscle cell; TF, tissue factor; TM, thrombomodulin.