Implication of hepatic sinusoidal cells in pathophysiology of the liver diseases and development of novel therapeutic strategies

肝窦细胞在肝脏疾病病理生理学中的意义及新治疗策略的开发

基本信息

批准号：
06454383
负责人：
ARII Shigeki
金额：
$ 4.61万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

1. Mechanism on endotoxin-induced liver injury. We clarified that ICAM-1 expression in the hepatic sinusoidal endothelial cell (SEC) was increased and then such increase was inhibited by a blockade of hepatic macrophages in endotoxin-injected rats. Also, we showed the amelioration of endotoxin-induced liver injury in the leucocytes-depletion rats. These evidence suggested the causative role of the interaction among hepatic macrophage, adhesion molecule and leucocytes in this injury. Furthermore, we identified thromboxane (TX) A_2 receptor (R) on SEC and showed pathogenic implication of TXA_2-TXA_2R system in endotoxin-induced and cold preservation/reperfusion liver injury.2. Pathogenesis of cold preservation-reperfusion liver injury. We found that hepatic macrophage is at priming state in the cold preservation of the liver. Then, it was shown that a blockade of hepatic macrophage suppressed intrasinusoidal coagulation and leucocyte adhesion in the liver, leading to the inhibition of hepatic microcirculatory disturbance.3. Expression of the Na^+/Ca^<++> exchanger in activated Ito cells. We demonstrated first that Na^+/Ca^<++> exchanger, which is a transporter protein that couples the translocation of Ca^<++> to that of Na^+ in the opposite direction and contribute to the maintenance of intracelluler Ca^<++> homeostasis, is expressed in Ito cells in association with liver fibrosis.4. Identification of kan-1 and its clinical implication. We identified a novel gene, kan-1 in the rat liver using an RNA-PCR cloning strategy. By cross-hybridyzation with a rat kan-1 cDNA probe, we obtained a cDNA clone from a human liver cDNA library. This is found to be identical to bile acid CoA : amino acid N-acyltransferase. We showed that kan-1 is a novel predictive indicator for prognosis of hepatoma patients.

1。内毒素诱导的肝损伤的机制。我们澄清说，肝弦正弦内皮细胞（SEC）中的ICAM-1表达增加了，然后在注入内毒素的大鼠中阻断肝巨噬细胞的封锁抑制了这种增加。另外，我们显示了内毒素诱导的肝损伤在白细胞止血大鼠中的改善。这些证据表明，肝巨噬细胞，粘附分子和白细胞在这种损伤中相互作用的作用。此外，我们在SEC上确定了血栓烷（TX）A_2受体（R），并显示了TXA_2-TXA_2R系统在内毒素诱导的和冷保存/再灌注肝损伤中的致病意义。2。冷保存重新灌注肝损伤的发病机理。我们发现，肝巨噬细胞处于肝脏冷保存中的启动状态。然后，结果表明，肝巨噬细胞的阻塞抑制了肝脏内侧内凝结和白细胞粘附，导致肝微循环障碍的抑制。3。激活的ITO细胞中Na^+/Ca^<++>交换器的表达。我们首先证明了Na^+/ca^<++>交换器，它是一种转运蛋白，将Ca^<++>的易位沿相反方向耦合到Na^+的转运，并有助于维持纤维内Ca ^<++>稳态，在ITO细胞中与肝纤维化相关。4。 KAN-1及其临床意义的识别。我们使用RNA-PCR克隆策略确定了大鼠肝脏中的新基因KAN-1。通过用大鼠KAN-1 cDNA探针交叉杂交杂志，我们从人肝cDNA文库中获得了cDNA克隆。发现这与胆汁酸COA相同：氨基酸N-酰基转移酶。我们表明KAN-1是肝癌患者预后的新型预测指标。