the potential relevance of endothelial activation biomarkers to sepsis has been raised in both this journal and others [ 1 - 3 ] .
biomarkers for sepsis associated with the endothelial glycocalyx remain relatively unknown , however , and this commentary attempts to reverse this omission .
the term glycocalyx ( sweet husk ) was introduced 50 years ago to describe an extracellular polysaccharide coating of cells .
whilst electron microscopy revealed that the luminal surface of the endothelium expressed this structure , it was thought to be of little consequence or functional significance .
what has become increasingly evident , however , is that the glycocalyx - now estimated to extend up to 1 m from the endothelial cell membrane - represents a substantial intravascular compartment contributing significantly to vascular wall homeostasis .
specifically , roles of the glycocalyx include maintenance of the vascular permeability barrier , mediation of shear - stress - dependent nitric oxide production , and housing vascular protective enzymes ( for example , superoxide dismutase ) and a wide array of coagulation inhibition factors such as antithrombin , the protein c system and tissue factor pathway inhibitor .
the glycocalyx also modulates the inflammatory response by preventing leukocyte adhesion and binding numerous ligands , including chemokines , cytokines and growth factors [ 4 - 6 ] .
negatively charged and with a mesh - like structure , the endothelial glycocalyx is comprised of glycoproteins , proteoglycans , glycosaminoglycans ( gags ) and associated plasma proteins including albumin .
proteoglycans consisting of a core membrane - bound protein of the syndecan or glypican families with attached heparan or chondroitin sulphate gag side chains are a prominent feature .
hyaluronan - a nonsulphated , uncharged gag with water - retaining properties - is attached or adsorbed onto other cell - surface anchored proteins ( for example , cd44 ) and helps to stabilise the glycocalyx structure .
alteration in the composition of the glycocalyx following exposure to an inflammatory insult is one of the earliest features of endothelial activation .
it is now accepted that tnf , oxidised lipoproteins , lipopolysaccharide , thrombin , ischaemia / reperfusion , hyperglycaemia and growth factors all cause glycocalyx disruption via the action of proteases   - leading either to partial degradation with release of gag side chains , or to more severe damage characterised by shedding of core proteins .
several studies have evaluated circulating levels of syndecan-1 and gags in patients with sepsis [ 10 - 13 ] .
plasma gag levels were higher in patients with septic shock than in matched controls , and were significantly higher in nonsurvivors .
in the same study , syndecan-1 levels were also increased and correlated with the sequential organ failure assessment score . in an additional study of 150 patients either with severe sepsis or septic shock or post - abdominal surgery without the systemic inflammatory response syndrome and healthy volunteers , significant increases in plasma syndecan-1 and heparan sulphate were observed in the sepsis and surgery groups .
the highest syndecan-1 levels were detected in patients with sepsis and correlated with those of il-6 .
a further study showed greater syndecan-1 levels in patients with septic shock compared with healthy controls , together with a positive correlation with vascular adhesion protein-1 and with day 1 sequential organ failure assessment scores .
finally , hyaluronan levels , in addition to those of syndecan-1 and heparan sulphate , have been shown to increase with severity of sepsis . whilst the care of patients with sepsis has improved over the last decade
the failure of two promising drugs , eritoran tetrasodium and drotrecogin alfa , to confer significant reduction in mortality suggests that novel approaches to sepsis research are required .
given the fundamental , but perhaps relatively overlooked , role of the endothelial glycocalyx in regulating vascular integrity and functions central to the pathophysiology of sepsis , identifying interventions aimed at protecting or repairing it might prove a promising therapeutic target .
some clinically established therapies used for the treatment of sepsis ( such as glucose control and steroid administration ) and also approaches used in experimental studies ( such as tnf inhibition , antithrombin iii , infusion of albumin and avoidance of natriuretic peptide release ) are known to reduce glycocalyx disruption .
however , drugs that might specifically increase the synthesis of glycocalyx components , refurbish the glycocalyx or selectively prevent protease degradation are not currently available
. future endeavours in the field of sepsis research , which are urgently required , should not only include components of the endothelial glycocalyx in the list of biomarkers , but also consider their potential as therapeutic targets for the development of new therapies .
 sepsis is the third largest cause of death in industrialised countries , but treatment remains largely supportive and effective therapeutic interventions are urgently needed . 
 disruption and dysfunction of the microvascular endothelium leading directly or indirectly to multiple organ failure are now recognised to underpin the pathophysiology of sepsis . 
 biomarkers of endothelial activation may therefore assume an important role in guiding future research efforts . 
 we suggest that integral to this approach is the investigation and evaluation of endothelial glycocalyx biomarkers , not only as indicators of the pathogenic process but also to inform the development of pharmacological and other therapies . 
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