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

在肝窦内皮细胞中，最重要的抗凝因子组织因子通路抑制剂（TFPI）和血栓调节蛋白的表达与其他器官外周血管中的表达相比，显著降低。本研究试图在肝窦壁上选择性表达外源性TFPI和携带血栓调节蛋白基因的胶束，以治疗大鼠原位肝移植（OLTX）后肝损伤。大鼠静脉注射重组人TFPI后，注射后迅速从循环中消失，但在肝窦内皮细胞和肝细胞微绒毛表面电镜下检测到。静脉注射肝素钠后，TFPI在血浆中重新出现，在肝窦壁上消失。聚乙烯醇糖在水中形成胶束，糖链在外面。该胶束可携带血栓调节蛋白。更多cDNA在其中心偶联SV40病毒启动子。将表面含有甘露糖和FITC等甘露糖胶束经大鼠门静脉注射后，沿窦壁内壁可见荧光产物，提示这些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凝血调节蛋白cDNA组成的胶束将可用于治疗内皮细胞明显破坏的OLTX后肝损伤。在治疗OLTX后的窦状纤维蛋白沉积时，刺激窦状内皮细胞的增殖也是可取的。最近，我们证明了窦状内皮细胞的增殖过程可能通过再生肝细胞、活化的Kupffer细胞和肝星状细胞产生的VEGF来调节。基于这些结果，我们现在正试图通过调节VEGF及其受体的表达来设计一种治疗窦状纤维蛋白沉积的新策略。少

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