Endothelial glycocalyx degradation during sepsis: Causes and consequences

Highlights • The endothelial glycocalyx is a ubiquitous intravascular structure essential for vascular homeostasis. • During sepsis, the glycocalyx is degraded via the collective action of a variety of redundant sheddases, the regulation of which remains the focus of active investigation. • Septic loss of the glycocalyx imparts both local vascular injury (leading to acute respiratory distress syndrome and acute kidney injury) as well as the systemic consequences of circulating glycosaminoglycan fragments (leading to cognitive dysfunction). • Glycocalyx degradation during sepsis is potentially shaped by clinically-modifiable factors, suggesting opportunities for therapeutic intervention to mitigate the end-organ consequences of sepsis.
The glycocalyx is a ubiquitous structure found on endothelial cells that extends into the vascular lumen. It is enriched in proteoglycans, which are proteins attached to the glycosaminoglycans heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronic acid. In health and disease, the endothelial glycocalyx is a central regulator of vascular permeability, inflammation, coagulation, and circulatory tonicity. During sepsis, a life-threatening syndrome seen commonly in hospitalized patients, the endothelial glycocalyx is degraded, significantly contributing to its many clinical manifestations. In this review we discuss the intrinsically linked mechanisms responsible for septic endothelial glycocalyx destruction: glycosaminoglycan degradation and proteoglycan cleavage. We then examine the consequences of local endothelial glycocalyx loss to several organ systems and the systemic consequences of shed glycocalyx constituents. Last, we explore clinically relevant non-modifiable and modifiable factors that exacerbate or protect against endothelial glycocalyx shedding during sepsis.