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

1.内毒素致肝损伤的机制。我们阐明，ICAM-1的表达在肝窦内皮细胞（SEC）的增加，然后这种增加被抑制肝巨噬细胞在内毒素注射大鼠的封锁。此外，我们还显示了白细胞耗竭大鼠内毒素诱导的肝损伤的改善。提示肝巨噬细胞、粘附分子和白细胞之间的相互作用在肝损伤中起重要作用。进一步鉴定SEC上血栓素（TXA_2）受体（R），揭示TXA_2-TXA_2R系统在内毒素诱导的肝损伤和冷保存/再灌注肝损伤中的致病作用.冷灌注肝损伤的发病机制。我们发现，在肝脏冷保存过程中，肝脏巨噬细胞处于启动状态。阻断肝巨噬细胞可抑制肝窦内凝血和白细胞粘附，从而抑制肝微循环障碍. Na^+/Ca^+<++>交换体在激活的Ito细胞中的表达。我们首次证实了Na^+/Ca^<++>交换蛋白在肝纤维化相关的Ito细胞中表达，它是一种转运蛋白，可将Ca^<++>转运与Na^+转运反向偶联，并有助于维持细胞内Ca^<++>稳态。kan-1的鉴定及其临床意义。我们使用RNA-PCR克隆策略在大鼠肝脏中发现了一个新基因kan-1。通过与大鼠kan-1 cDNA探针杂交，我们从人肝cDNA文库中获得了一个cDNA克隆。发现这与胆汁酸CoA：氨基酸N-酰基转移酶相同。我们发现kan-1是一种新的预测肝癌患者预后的指标。

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.