Regulation of platelet-leukocyte interaction and pharmaceutical application

血小板-白细胞相互作用的调节及药物应用

• 批准号: 13557213
• 负责人: TSUJI Tsutomu
• 金额: $ 3.97万
• 依托单位: Hoshi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557213/
• 关键词: P-selectin; Cell adhesion; Platelet; Leukocyte; Reactive oxygen species; Sialic acid; Sulfated carbohydrate; Hemodialysis; 抗接着療法; 活性酸素; 生体適合性; 炎症反応; 腫瘍壊死因子; 細胞表面糖鎖

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.

P-选择素介导血小板/内皮细胞和白细胞之间的细胞粘附，并且在白细胞募集到出血和炎症部位中起关键作用。此外，相互作用导致白细胞的功能活化，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，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活化。1.唾液酸硫酸化衍生物对P-选择素介导的细胞粘附的抑制：我们检测了合成的唾液酸硫酸化衍生物（NMSO 3）对P-选择素介导的细胞粘附的影响，并发现了以下结果。1)P-selectin/IgG嵌合体与纯化的P-selectin糖蛋白配体-1的结合被可溶性NMSO 3抑制。2)NMSO 3可抑制HL 60细胞与表达P-选择素的CHO细胞的粘附。3)NMSO 3抑制单核细胞中P-选择素诱导的肿瘤坏死因子-α的产生，并激活血小板诱导的中性粒细胞中活性氧的产生。结论：NMSO 3是P-选择素介导的细胞粘附和粘附依赖性白细胞活化的特异性抑制剂。2.血液透析过程中白细胞通过与活化的血小板粘附而活化：与疏水材料组成的透析膜接触比与亲水材料组成的透析膜接触更容易活化血小板。活化的血小板粘附于白细胞并诱导白细胞产生ROS。因此，血小板与血液透析膜之间的相互作用是决定其生物相容性的关键因素之一。

项目成果

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Ogawa Y, Iwama M, Ohgi K, Tsuji T, Irie M, Itagaki T, Kobayashi H, Jnokuchi N: "Effect of replacing the aspartic acid/glutamic acid residues of bullfrog sialic acid binding lectin with asparagine/glutamine and arginine on the inhibition of cell proliferat

Okawa Y、Iwama M、Ohgi K、Tsuji T、Irie M、Itagaki T、Kobayashi H、Jnokuchi N：“用天冬酰胺/谷氨酰胺和精氨酸取代牛蛙唾液酸结合凝集素的天冬氨酸/谷氨酸残基对抑制的影响

Tsuji T, Kawada Y, Kai-Murozono M, Komatsu S, Han SA, Takeuchi K, Mizusbima H, Miyazaki, K, Irimura T: "Regulation of melanoma cell migration and invasion by laminin-5 and α3β1 integrin (VLA-3)."Clin.ExMetastasis. 19. 127-134 (2002)

Tsuji T、Kawada Y、Kai-Murozono M、Komatsu S、Han SA、Takeuchi K、Mizusbima H、Miyazaki、K、Irimura T：“层粘连蛋白-5 和 α3β1 整合素 (VLA-3) 对黑色素瘤细胞迁移和侵袭的调节.“Clin.ExMetastasis.19. 127-134 (2002)

Shodai T, Suzuki J, Kudo S, Itoh S, Terada M, Fujita S, Shimazu H, Tsuji T: "Inhibition of P-selectin-mediated cell adhesion by a sulfated derivative of sialic acid."Biochem Biophys Res Commun. 312. 787-793 (2003)

Shodai T、Suzuki J、Kudo S、Itoh S、Terada M、Fujita S、Shimazu H、Tsuji T：“唾液酸的硫酸化衍生物抑制 P-选择素介导的细胞粘附。”Biochem Biophys Res Commun。