Anticoagulant Targeting the Hepatic Sinusoids for Liver Injury Following Orthotopic Liver Transplantation

针对原位肝移植后肝损伤的肝正弦抗凝剂

• 批准号: 07670611
• 负责人: MOCHIDA Satoshi
• 金额: $ 1.6万
• 依托单位: Saitama Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07670611/
• 关键词: Liver transplantation; Liver failure; Sinusoidal endothelial cell; Thrombomodulin; TFPI; VEGF; 類洞内皮細胞

In endothelial cells of the hepatic sinusoids, the expression of tissue factor pathway inhibitor (TFPI) and thrombomodulin, most important anticoagulant factors, are extremely decreased compared to those in peripheral blood vessels in other ortans. The present study was attempted to express exogenous TFPI and micelles carrying thrombomodulin gene selectively on hepatic sinusoidal walls for the treatment of liver injury following orthotopic liver transplantation (OLTX) in rats.When rats received recombinant human TFPI intravenously, it disappeared from the circulation rapidly after the injection, but was detected electron microscopically on the surface of sinusoidal endothelial cells and microvilli of hepatocytes in the space of Disse. In these rats, the TFPI reappeared in the plasma and disappeared from the hepatic sinusoidal walls by intravenous injection of heparin sodium. Polyvinyl sugar forms a micelle in water with sugar chains on the outside. This micelle can carry thrombomodulin … More cDNA coupled with SV40 virus promoter in its center. When such micelles containing mannose as sugar and FITC on the surface were injected via the portal vein in rats, fluorescent products were seen along the lining of sinusoidal walls, suggesting that the micelles were trapped by mannose receptors on the surface of sinusoidal walls. Thus, exogenous TFPI and micelles consisting of polyvinyl mannose and thrombomodulin cDNA would be available for the therapy of liver injury following OLTX where endothelial cells are markedly destroyed.In the treatment of sinusoidal fibrin deposition following OLTX,stimulation of proliferation of sinusoidal endothelial cells would be also desirable. Recently, we demonstrated that the proliferative process of sinusoidal endothelial cells may be regulated through VEGF produced by regenerating hepatocytes, activated Kupffer cells and hepatic stellate cells. Based on these results, we are now trying to devise a novel strategy for the treatment of sinusoidal fibrin deposition by regulating the expressions of VEGF and its receptors. Less

在肝窦内皮细胞中，最重要的抗凝因子组织因子途径抑制物（TFPI）和血栓调节蛋白的表达与其他器官的外周血管相比显著降低。本研究尝试在大鼠肝窦壁选择性表达外源性TFPI和携带血栓调节蛋白基因的胶束，用于治疗大鼠原位肝移植（OLTX）后的肝损伤。电镜下可见肝窦内皮细胞表面及肝细胞微绒毛。在这些大鼠中，TFPI重新出现在血浆中，并通过静脉注射肝素钠从肝窦壁消失。聚乙烯基糖在水中形成胶束，糖链在外面。这种胶束可以携带血栓调节蛋白 ...更多信息 其中心偶联有SV40病毒启动子的cDNA。将表面含糖甘露糖和FITC的胶束经门静脉注入大鼠肝窦后，可沿着窦壁内壁观察到荧光产物，提示胶束被窦壁表面的甘露糖受体捕获。因此，外源性TFPI和由聚乙烯甘露糖和血栓调节蛋白cDNA组成的胶束将可用于治疗OLTX后的肝损伤，其中内皮细胞被显著破坏。在治疗OLTX后的窦状隙纤维蛋白沉积时，刺激窦状隙内皮细胞的增殖也是期望的。最近，我们发现肝窦内皮细胞的增殖过程可能通过再生肝细胞、激活的枯否细胞和肝星状细胞产生的VEGF来调节。基于这些结果，我们现在正试图设计一种新的策略，通过调节VEGF及其受体的表达来治疗窦状隙纤维蛋白沉积。少

项目成果

Fujiwara K,Mochida S,et al.: "Use of Prostaqlandin I2 analog in the treatment of massive hepatic necrosis associated with endothelial injury and diffuse sinusoidal Fibrin deposition." Dig Dis Sci. 40. 41-47 (1995)

Fujiwara K、Mochida S 等人：“使用 Prostaqlandin I2 类似物治疗与内皮损伤和弥漫性肝窦纤维蛋白沉积相关的大量肝坏死。”

Arai M,Mochida S,Ohno A,Fujiwara K.: "Blood coagulation in the hepatic sinusoids as a factor of liver injury following orthotopic liver transplantation in rats." Transplantation. 62. 1398-1401 (1996)

Arai M、Mochida S、Ohno A、Fujiwara K.：“肝窦中的血液凝固是大鼠原位肝移植后肝损伤的一个因素。”

Fujiwara K,Mochida S,et al.: "Use of Prostaglandin I2 analog in the treatment of massive hepatic necrosis associated with endothelial injury and diffuse sinusoidal tibrin deposition." Dig Dis Sci. 40. 41-47 (1995)

Fujiwara K、Mochida S 等人：“使用前列腺素 I2 类似物治疗与内皮损伤和弥漫性肝窦 tibrin 沉积相关的大量肝坏死。”

Arai M,Mochida S,Ohno A,Fujiwara K.: "Blood coaqulation in the hepatic sinusoids as a factor of liver injury following orthotopic liver transplantation in rats." Transplantation. 62. 1398-1401 (1996)

Arai M、Mochida S、Ohno A、Fujiwara K.：“肝窦中的血液凝固是大鼠原位肝移植后肝损伤的一个因素。”

Mochida S,Ohno A,Arai M,Tamatani T,Miyasaka M,Fujiwara K.: "Role of Adhesion Molecules in the Development of Massive Hepatic Necrosis in Rats" Hepatology. 23. 320-328 (1996)

Mochida S、Ohno A、Arai M、Tamatani T、Miyasaka M、Fujiwara K.：“粘附分子在大鼠大面积肝坏死发展中的作用”肝病学。