Targeting the "sweet spot" in septic shock - A perspective on the endothelial glycocalyx regulating proteins Heparanase-1 and -2

Abstract

Sepsis is a life-threatening syndrome caused by a pathological host response to an infection that eventually, if uncontrolled, leads to septic shock and ultimately, death. In sepsis, a massive aggregation of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) cause a cytokine storm. The endothelial glycocalyx (eGC) is a gel like layer on the luminal side of the endothelium that consists of proteoglycans, glycosaminoglycans (GAG) and plasma proteins. It is synthesized by endothelial cells and plays an active role in the regulation of inflammation, permeability, and coagulation. In sepsis, early and profound injury of the eGC is observed and circulating eGC components correlate directly with clinical severity and outcome. The activity of the heparan sulfate (HS) specific glucuronidase Heparanase-1 (Hpa-1) is elevated in sepsis, resulting in shedding of heparan sulfate (HS), a main GAG of the eGC. HS induces endothelial barrier breakdown and accelerates systemic inflammation. Lipopolysaccharide (LPS), a PAMP mainly found on the surface of gram-negative bacteria, activates TLR-4, which results in cytokine production and further activation of Hpa-1. Hpa-1 shed HS fragments act as DAMPs themselves, leading to a vicious cycle of inflammation and end-organ dysfunction such as septic cardiomyopathy and encephalopathy. Recently, Hpa-1's natural antagonist, Heparanase-2 (Hpa-2) has been identified. It has no intrinsic enzymatic activity but instead acts by reducing inflammation. Hpa-2 levels are reduced in septic mice and patients, leading to an acquired imbalance of Hpa-1 and Hpa-2 paving the road towards a therapeutic intervention. Recently, the synthetic antimicrobial peptide 19-2.5 was described as a promising therapy protecting the eGC by inhibition of Hpa-1 activity and HS shed fragments in animal studies. However, a recombinant Hpa-2 therapy does not exist to the present time. Therapeutic plasma exchange (TPE), a modality already tested in clinical practice, effectively removes injurious mediators, e.g., Hpa-1, while replacing depleted protective molecules, e.g., Hpa-2. In critically ill patients with septic shock, TPE restores the physiological Hpa-1/Hpa-2 ratio and attenuates eGC breakdown. TPE results in a significant improvement in hemodynamic instability including reduced vasopressor requirement. Although promising, further studies are needed to determine the therapeutic impact of TPE in septic shock.