THE ENDOTHELIUM IN SEPSIS

Abstract

Sepsis affects practically all aspects of endothelial cell (EC) function and is thought to be the key factor in the progression from sepsis to organ failure. Endothelial functions affected by sepsis include vasoregulation, barrier function, inflammation, and hemostasis. These are among other mechanisms often mediated by glycocalyx shedding, such as abnormal nitric oxide metabolism, up-regulation of reactive oxygen species generation due to down-regulation of endothelial-associated antioxidant defenses, transcellular communication, proteases, exposure of adhesion molecules, and activation of tissue factor. This review covers current insight in EC-associated hemostatic responses to sepsis and the EC response to inflammation. The endothelial cell lining is highly heterogeneous between different organ systems and consequently also in its response to sepsis. In this context, we discuss the response of the endothelial cell lining to sepsis in the kidney, liver, and lung. Finally, we discuss evidence as to whether the EC response to sepsis is adaptive or maladaptive. This study is a result of an Acute Dialysis Quality Initiative XIV Sepsis Workgroup meeting held in Bogota, Columbia, between October 12 and 15, 2014.

Fig. 1. The endothelium in health

This figure shows a number of the key elements of the endothelium in health responsible for its key role in its interface between circulating blood and the parenchymal cells. Elements relating to it function as a vascular barrier, vascular regulation, transcellular signaling, and hemostasis are shown. Highlighted are the endothelium glycocalyx housing various molecules, including mechanotransducers (and its transducer role between sensing sheer stress and inducing NO affective for smooth muscle vasodilation, inactive adhesion molecules embedded in the glycocalyx, molecules essential for hemostatic, and antioxidant defense molecules such as SOD). Intra and transcellular elements of the endothelial shown include mitochondria, with its contribution to ROS generation and oxidative phosphorylation. Transcellular elements present include gap junctions for electrical communication for upstream vascular regulation and intercellular tight junctions important for maintaining vascular barrier. Morphological elements shown include transcellular fenestrations and pores. Source: Acute Dialysis Quality Initiative 14, www.ADQI.net 2014; used with permission.

Fig. 2. The endothelium in sepsis

This figure shows the pathogenic effect of sepsis on the various elements of the ECL resulting in its functional impairment in terms of its function as a vascular barrier, a regulator of vasotone, and its hemostatic function. The destruction of the glycocalyx results, among many other effects, in the exposure of adhesion molecules, resulting in the trapping (selectins) and transmigration (integrins) of activated leukocytes, activation of hemostatic compounds in favor of a proprocoagulant state, and the loss of mechanotransducer function due to these molecules, losing their natural environment essential for the sensing of sheer stress. The barrier function of the ECL is compromised by direct membrane destruction due to lipid peroxidation induced by ROS/RNS, as well as the decomposition of molecules such as tight junctions anchoring the EC together. The role of the EC as a vasomotor tone regular is lost due to the loss of function of the mechanotransducer system, the overproduction of iNOS-mediated NO, and the loss of transcellular gap junction essential for an integrative control of vasotone along the ECL. Endothelial destruction also results in the release of microparticles contributing to the pathogenic effect of EC dysfunction. Source: Acute Dialysis Quality Initiative 14, www.ADQI.net 2014; used with permission. iNOS indicates inducible nitric oxide synthase; RNS, reactive nitrogen species.

Fig. 3. Adaptive versus maladaptive response to sepsis

Source: Acute Dialysis Quality Initiative 14, www.ADQI.net 2014; used with permission.