The Endothelial Glycocalyx: New Diagnostic and Therapeutic Approaches in Sepsis

Abstract

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The endothelial glycocalyx is one of the earliest sites involved during sepsis. This fragile layer is a complex network of cell-bound proteoglycans, glycosaminoglycan side chains, and sialoproteins lining the luminal side of endothelial cells with a thickness of about 1 to 3 μm. Sepsis-associated alterations of its structure affect endothelial permeability and result in the liberation of endogenous damage-associated molecular patterns (DAMPs). Once liberated in the circulatory system, DAMPs trigger the devastating consequences of the proinflammatory cascades in sepsis and septic shock. In this way, the injury to the glycocalyx with the consecutive release of DAMPs contributes to a number of specific clinical effects of sepsis, including acute kidney injury, respiratory failure, and septic cardiomyopathy. Moreover, the extent of glycocalyx degradation serves as a marker of endothelial dysfunction and sepsis severity. In this review, we highlight the crucial role of the glycocalyx in sepsis as a diagnostic tool and discuss the potential of members of the endothelial glycocalyx serving as hopeful therapeutic targets in sepsis-associated multiple organ failures.

Figure 1

Model of proinflammatory response induced by heparanase. Heparanase cleaves and solubilizes heparan sulfate (HS) fragments from their proteoglycan (HSPG) within highly sulfated regions. Analogue to LPS, HS fragments then signal through MyD88-dependent receptors, of which TLR-4 is one, and this leads to NF-kappaB cleavage and activation. NF-kappaB-dependent upregulation leads to the release of cytokine production including interleukin-6 (IL-6). Cytokines are involved in activating heparanase, thereby enhancing the devastating circle of an inflammatory response.

Figure 2

Heparanase level (a) and activity (b) in human sepsis (n = 18) and healthy volunteers (n = 10). Patients with Gram-negative (n = 10) septic shock show higher levels of heparanase and higher heparanase activity, compared to those suffering from Gram-positive (n = 8) septic shock (modified from [11]).

Figure 3

Heparan sulfate levels in human sepsis (n = 18) and healthy volunteers (n = 10). Patients with Gram-negative (n = 10) septic shock show higher levels of heparan sulfates, compared to those suffering from Gram-positive (n = 8) septic shock (modified from [10]).