Role of the Glycocalyx as a Barrier to Leukocyte-Endothelium Adhesion

Leukocyte (WBC) to endothelial cell (EC) adhesion is a receptor-mediated process governed by the avidity and affinity of selectins, which modulate adhesive forces during WBC rolling, and integrins, which determine the strength of firm adhesion. Adhesion receptors on the EC surface lie below an endothelial surface layer (ESL) comprised of the EC glycocalyx and adsorbed proteins which, in vivo, have a thickness on the order 500 nm. The glycocalyx consists of a matrix of the glycosaminoglycans heparan sulfate and chondroitin sulfate, bound to proteoglycans and encased in hyaluronan. Together, these carbohydrates form a layer that varies in glycan content along the length of post-capillary venules where WBC-EC adhesion occurs. Thickness and porosity of the glycocalyx can vary dramatically during the inflammatory response as observed by increased infiltration and diffusion of macromolecules within the layer following activation of the EC by cytokines and chemoattractants. In models of inflammation in the living animal, the shedding of glycans and diminished thickness of the glycocalyx rapidly occur to facilitate penetration by the WBCs and adhesion to the EC. The primary effectors of glycan shedding appear to be metalloproteases and heparanase released by the EC. Retardation of glycan shedding and WBC-EC adhesion has been demonstrated in vivo using MMP inhibitors and low-molecular-weight heparin (LMWH), where the latter competitively binds to heparanase liberated by the EC. Together, these agents may serve to stabilize the ESL and provide a useful strategy for treatment of inflammatory disorders.