Regulation of platelet-leukocyte interaction and pharmaceutical application

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P-selectin mediates cell adhesion between platelets/endothelial cells and leukocytes, and plays a crucial role in the recruitment of leukocytes into hemorrhagic and inflammatory sites. Furthermore, the interaction causes the functional activation of leukocytes including reactive oxygen species (ROS) and cytokine production by leukocytes. In this study, 1) we attempted to regulate the interaction by a carbohydrate-based inhibitor, and 2) we characterized the leukocyte activation caused by the platelet-leukocyte interaction during hemodialysis.1.Inhibition of P-selectin-mediated cell adhesion by a sulfated derivative of sialic acid : We examined effects of a synthetic sulfated derivative of sialic acid (NMSO3) on P-selectin-mediated cell adhesion and found the following. 1) The binding of P-selectin/IgG chimera to purified P-selectin glycoprotein ligand-1 was inhibited by soluble NMSO3. 2) The adhesion of HL6O cells to P-selectin-expressing CHO cells was inhibited by NMSO3. 3) NMSO3 inhibited P-selectin-induced tumor necrosis factor-α production in monocytes and activated platelet-induced generation of reactive oxygen species in neutrophils. In conclusion, NMSO3 acts as a specific inhibitor for P-selectin-mediated cell adhesion and for adhesion-dependent leukocyte activation.2.Leukocyte activation through the adhesion with activated platelets during hemodialysis : Platelets were more easily activated by the contact with dialyzer membranes composed of hydrophobic materials than by that of hydrophilic materials. The activated platelets then adhered to leukocytes and induced ROS production by leukocytes. Therefore, the interaction between platelets and hemodialysis membranes is one of the key factors to determine their biocompatibility.