Study on Strategies for Non-Heart Beating Liver

肝脏无心跳治疗策略研究

基本信息

批准号：
11470137
负责人：
FUJIWARA Kenji
金额：
$ 4.54万
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 (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470137/
关键词：
Liver transplantation Microcirculatory disturbance Sinusoidal endothelial cell Kupffer cell Stellate cell VEGF Osteopontin Transgenic mouse 肝類洞内皮細胞肝星細胞 angiopoiein Tie受容体 osteopontin 肝再生 Angiopoietin TIE受容体肝移植後肝不全 peric

项目摘要

Sinusoidal endothelial cell (SEC) injury is a major abnormality in the liver transplanted from non-heart beating donors. It is important to protect SECs for the establishment of non-heartbcating liver transplantationVEGF is a factor essential for maintenance as well as proliferation of SECs in primary culture. We demonstrated that VEGF also acted as avascular permeability factor through up-regulation of the porosity on SECs. Furthermore, VEGF inhibited contraction of stellate cells, pericytes of SECs, suggesting that VEGF can regulate microcirculation in the hepatic sinusoids. VEGF expression in hepatocytes was increased in rat liver after cold preservation in UW solution, but mRNA expressions of VBGFR-1 and VEGFR-1 were decreased prior to the development of SEC in jury These results may suggest that VEGF cannot work effectively on SECs in the cold preserved liver, and also that exogenous VBGF cannot prevent SEC from injuryKupffer cells were markedly activated in the cold preserved liver, and this activation contributed to SEC injury after orthotopic transplantation of such livers. We found that activated Kupffer cells expressed osteopontin an essential cytokine for initiation of Th1 immune response. Also, we demonstrated that osteopontin played a major role as a chemokine in macrophage migration into the liver using mice with different alleles of osteopontin gene, suggesting that the modulation of osteopontin expression in Kupffer cells may be another strategy for protection of the SECs. We made transgenic mice expressing osteopontin very highly in the liver using human serum amyloid P component promotor as a vector specific for hepatocytes Investigations to prove our hypothesis are now in progress

正弦内皮细胞（SEC）损伤是无心跳供体移植肝脏的主要异常。保护SEC对于非心跳肝移植的建立非常重要。VEGF是原代培养中SEC的维持和增殖所必需的因素。我们证明 VEGF 还可以通过上调 SEC 的孔隙率发挥无血管通透性因子的作用。此外，VEGF抑制星状细胞、SEC周细胞的收缩，表明VEGF可以调节肝窦的微循环。在UW溶液中冷保存后，大鼠肝脏中肝细胞中的VEGF表达增加，但在损伤中SEC发生之前，VBGFR-1和VEGFR-1的mRNA表达降低。这些结果可能表明VEGF不能在大鼠肝脏中有效地作用于SEC。冷保存肝脏中Kupffer细胞明显活化，且外源性VBGF不能防止SEC损伤。Kupffer细胞在冷保存肝脏中显着活化，这种活化导致了此类肝脏原位移植后的SEC损伤。我们发现活化的库普弗细胞表达骨桥蛋白，骨桥蛋白是启动 Th1 免疫反应的重要细胞因子。此外，我们使用具有不同骨桥蛋白基因等位基因的小鼠证明骨桥蛋白作为趋化因子在巨噬细胞迁移到肝脏中发挥着重要作用，这表明调节Kupffer细胞中的骨桥蛋白表达可能是保护SEC的另一种策略。我们使用人血清淀粉样蛋白 P 成分启动子作为肝细胞特异性载体，制作了在肝脏中高度表达骨桥蛋白的转基因小鼠。证明我们假设的研究正在进行中