Shared Features of Endothelial Dysfunction between Sepsis and Its Preceding Risk Factors (Aging and Chronic Disease)

Abstract

Acute vascular endothelial dysfunction is a central event in the pathogenesis of sepsis, increasing vascular permeability, promoting activation of the coagulation cascade, tissue edema and compromising perfusion of vital organs. Aging and chronic diseases (hypertension, dyslipidaemia, diabetes mellitus, chronic kidney disease, cardiovascular disease, cerebrovascular disease, chronic pulmonary disease, liver disease, or cancer) are recognized risk factors for sepsis. In this article we review the features of endothelial dysfunction shared by sepsis, aging and the chronic conditions preceding this disease. Clinical studies and review articles on endothelial dysfunction in sepsis, aging and chronic diseases available in PubMed were considered. The main features of endothelial dysfunction shared by sepsis, aging and chronic diseases were: (1) increased oxidative stress and systemic inflammation, (2) glycocalyx degradation and shedding, (3) disassembly of intercellular junctions, endothelial cell death, blood-tissue barrier disruption, (4) enhanced leukocyte adhesion and extravasation, (5) induction of a pro-coagulant and anti-fibrinolytic state. In addition, chronic diseases impair the mechanisms of endothelial reparation. In conclusion, sepsis, aging and chronic diseases induce similar features of endothelial dysfunction. The potential contribution of pre-existent endothelial dysfunction to sepsis pathogenesis deserves to be further investigated.

Keywords: aging; chronic disease; endothelium dysfunction; sepsis.

Figure 1

The endothelium in different scenarios: (A) Healthy endothelium: the normal vascular endothelium consists of a layer of endothelial cells with the glycocalyx on the luminal side. It prevents microorganisms to enter into tissues, exerting in addition a natural anticoagulant action that prevents from uncontrolled activation of the coagulation system; (B) Endothelial dysfunction (ED) induced by aging and chronic disease: senescence and the comorbidities preceding sepsis are associated to the presence of a chronic status of increased oxidative stress and inflammation, which induces glicocalyx degradation, apoptosis of endothelial cells, disassembly of endothelial cell junctions, and increased expression of molecules which promotes leukocyte adhesion to endothelial cells. In turn, these diseases induce a pro-coagulant and anti-fibrinolytic state with diminished activation of protein C and increased production of tissue factor. Decrease in the production of nitric oxyde by the endothelial nitric oxide synthase promotes platelet aggregation and adhesion. Finally, these diseases impair production and function of Endothelial Progenitor Cells, impairing endothelial regeneration; (C) ED in sepsis: sepsis induces similar features of ED to those caused by aging and chronic diseases, inducing oxidative stress and inflammation, release of NETs and proteases by neutrophils, leading to fluid and cell leakage, hypotension, microvascular thrombosis, inadequate organ perfusion, organ failure and shock in the most severe cases. In addition, bacterial toxins can breach the endothelial barrier, by directly killing endothelial cells (ECs), weakening the cytoskeleton within ECs, and breaking the junctions between ECs. Acute challenges such as the aggression induced by surgery, trauma or hypervolemia could contribute to facilitate or enhance ED in patients facing an infection. Images for representing cells were taken from “Smart Servier Medical Art” (https://smart.servier.com/). NO: nitric oxide.

Figure 2

Proof of concept studies supporting the connection between chronic ED and sepsis. Images for representing mice were taken from “Smart Servier Medical Art” (https://smart.servier.com/). ICAM-1: intercellular adhesion molecule 1; VEGF: vascular endothelial growth factor; cGMP: cyclic guanosine monophosphate; sFLT-1: fms-like tyrosine kinase-1.

Figure 3

Potentially synergistic factors contributing to sepsis. Blue circle: immunological, coagulation or metabolic alterations previous to sepsis or induced by sepsis. Green circle: chronic endothelial dysfunction (ED) pre-sepsis caused by aging and chronic diseases. Orange circle: acute ED induced by sepsis secondary to microbial aggression, to the dysfunctional host response to infection, hypervolemia, trauma, surgery, and/or to other acute insults facilitating sepsis.