|Budget Amount *help
¥2,500,000 (Direct Cost : ¥2,500,000)
Fiscal Year 1996 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1995 : ¥2,000,000 (Direct Cost : ¥2,000,000)
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
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