Abstract
Significance: Under homeostatic conditions, the endothelium dynamically regulates vascular barrier function, coagulation pathways, leukocyte adhesion, and vasomotor tone. During sepsis and acute inflammation, endothelial cells (ECs) undergo multiple phenotypic and functional modifications that are initially adaptive but eventually become harmful, leading to microvascular dysfunction and multiorgan failure. Critical Issues and Recent Advances: Sepsis unbalances the redox homeostasis toward a pro-oxidant state, characterized by an excess production of reactive oxygen species and reactive nitrogen species, mitochondrial dysfunction, and a breakdown of antioxidant systems. In return, oxidative stress (OS) alters multiple EC functions and promotes a proinflammatory, procoagulant, and proadhesive phenotype. The OS also induces glycocalyx deterioration, cell death, increased permeability, and impaired vasoreactivity. Thus, during sepsis, the ECs are both a significant source and one of the main targets of OS. Future Directions: This review aims at covering the current understanding of the role of OS in the endothelial adaptive or maladaptive multifaceted response to sepsis and to outline the therapeutic potential and issues of targeting OS and endothelial dysfunction during sepsis and septic shock. One of the many challenges in the management of sepsis is now based on the detection and correction of these anomalies of endothelial function.
Highlights
Septic shock is defined as a condition whereby the circulation cannot deliver adequate blood flow to meet the tissue’s metabolic demand and/or cellular metabolism is impaired, leading to organ dysfunction [138]
Future Directions: This review aims at covering the current understanding of the role of oxidative stress (OS) in the endothelial adaptive or maladaptive multifaceted response to sepsis and to outline the therapeutic potential and issues of targeting OS and endothelial dysfunction during sepsis and septic shock
Microcirculatory anomalies are involved throughout the course of septic shock, and signs such as skin mottling on the knee area, prolonged capillary refill time (CRT), central-toperipheral temperature gradient, low tissue oxygen saturation (StO2), or abnormal sublingual perfusion index correlate with organ failure severity and are predictive of intensive care unit (ICU) mortality [7, 40, 47, 68]
Summary
Septic shock is defined as a condition whereby the circulation cannot deliver adequate blood flow to meet the tissue’s metabolic demand and/or cellular metabolism is impaired, leading to organ dysfunction [138]. Microcirculatory anomalies are involved throughout the course of septic shock, and signs such as skin mottling on the knee area, prolonged capillary refill time (CRT), central-toperipheral temperature gradient, low tissue oxygen saturation (StO2), or abnormal sublingual perfusion index correlate with organ failure severity and are predictive of intensive care unit (ICU) mortality [7, 40, 47, 68]. The substratum of microcirculatory failure is characterized by endothelial dysfunction, which is often referred to as sepsis-induced endotheliopathy. Sepsis causes glycocalyx (GCX) damage, dysregulated microcirculatory vasoreactivity, capillary leak, and impaired tissue perfusion [83]. OS contributes substantially to sepsis-induced endotheliopathy by playing a role in impaired vasomotricity, augmenting leukocyte and platelet adhesion to ECs and capillary permeability, and promoting cell death and a procoagulant state of the endothelium. This review aims at covering the current understanding of the role of OS in the adaptive or maladaptive multifaceted response to acute inflammation, and therapeutic avenues targeting OS and endothelial alterations during septic shock
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