Regulation of platelet-leukocyte interaction and pharmaceutical application

P-选择素介导了血小板/内皮细胞和白细胞之间的细胞黏附，并在白细胞募集到出血和炎症部位起着至关重要的作用。此外，这种相互作用还导致白细胞的功能激活，包括活性氧(ROS)和白细胞产生的细胞因子。在这项研究中，1)我们试图通过一种基于碳水化合物的抑制剂来调节这种相互作用，以及2)我们表征了血液透析过程中血小板-白细胞相互作用引起的白细胞激活。1.一种唾液酸硫酸酯类化合物抑制P-选择素介导的细胞黏附：我们研究了一种合成的唾液酸硫酸酯衍生物(NMSO3)对P-选择素介导的细胞黏附的影响，结果如下。1)可溶性NMSO3抑制P-选择素/免疫球蛋白嵌合体与纯化的P-选择素糖蛋白配体-1的结合。2)NMSO3抑制HL6O细胞与表达P-选择素的CHO细胞的黏附。3)NMSO3抑制P-选择素诱导的单核细胞肿瘤坏死因子-α的产生，激活血小板诱导的中性粒细胞产生的活性氧。结论：NMSO3是P-选择素介导的细胞黏附和黏附依赖的白细胞活化的特异性抑制剂。2.在血液透析过程中，通过与活化的血小板黏附而激活白细胞：与由疏水材料组成的透析膜接触时，血小板比亲水材料更容易被激活。激活的血小板随后与白细胞黏附，并诱导白细胞产生ROS。因此，血小板与血液透析膜的相互作用是决定其生物相容性的关键因素之一。

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.