Endothelial dysfunction: a therapeutic target in bacterial sepsis?

ABSTRACT

Introduction

Endothelial cells maintain vascular integrity, tone, and patency and have important roles in hemostasis and inflammatory responses. Although some degree of endothelial dysfunction with increased vascular permeability may be necessary to control local infection, excessive dysfunction plays a central role in the pathogenesis of sepsis-related organ dysfunction and failure as it results in dysregulated inflammation, vascular leakage, and abnormal coagulation. The vascular endothelium has thus been proposed as a potential target for therapeutic intervention in patients with sepsis.

Areas covered

Different mechanisms underlying sepsis-related dysfunction of the vascular endothelium are discussed, including glycocalyx shedding, nitrosative stress, and coagulation factors. Potential therapeutic implications of each mechanism are mentioned.

Expert opinion

Multiple targets to protect or restore endothelial function have been suggested, but endothelium-driven treatments remain a future potential at present. As some endothelial dysfunction and permeability may be necessary to remove infection and repair damaged tissue, targeting the endothelium may be a particular challenge. Ideally, therapies should be guided by biomarkers related to that specific pathway to ensure they are given only to patients most likely to respond. This enrichment based on biological plausibility and theragnostics will increase the likelihood of a beneficial response in individual patients and enable more personalized treatment.

KEYWORDS:

• Glycocalyx
• nitric oxide
• vasoconstriction
• permeability
• coagulopathy
• biomarker
• multiple organ failure
• sepsis
• endothelial dysfunction
• vascular endothelium

Abbreviations

ADH antidiuretic hormone

Angpt angiopoietin

APC activated protein C

DAMP damage-associated molecular pattern

DIC disseminated intravascular coagulopathy

ET-1 endothelin-1

HMGB1 high mobility group box 1 protein

MMP matrix metalloproteinase

NO nitric oxide

NOS nitric oxide synthase

PAF platelet activating factor

PAMP pathogen-associated molecular pattern

SAPS simplified acute physiology score

SOFA sequential organ failure assessment

TLR Toll-like receptor

VEGF vascular endothelial growth factor

Article highlights

• The vascular endothelium plays a key role in the regulation of vascular homeostasis (tone and permeability), hemostasis, and inflammation

• Endothelial cell function is disrupted in sepsis and this dysfunction has an important role in sepsis-related organ dysfunction

• Some degree of endothelial dysfunction is necessary to clear infection and repair tissue, but excessive, systemic dysfunction can be harmful

• Getting the balance right between allowing some adapted endothelial activation and permeability but avoiding excessive permeability may make targeting the endothelium with therapeutic interventions challenging.

• Multiple potential therapeutic strategies have been suggested that may protect or restore various aspects of endothelial function, but remain largely experimental. Current compounds of particular interest including unfractionated heparin, other coagulopathy-targeting drugs, vasopressin, and anti-inflammatory agents.

• Integrative monitoring combining measures of endothelial function at the cellular level with physiological variables and patient phenotypes is needed to help diagnose endothelial dysfunction, select most appropriate therapies for individual patients and monitor response to treatment.

Disclosure statement

No potential conflict of interest was reported by the authors.