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。我们明确了内毒素注射大鼠肝窦内皮细胞(SEC)ICAM-1的表达增加，并通过阻断肝巨噬细胞来抑制这种增加。此外，我们还显示了内毒素所致的肝损伤在白细胞耗竭大鼠中的改善作用。提示肝巨噬细胞、黏附分子和白细胞之间的相互作用在肝损伤中起重要作用。此外，我们在SEC上发现了血栓烷(TXA)A_2受体(R)，并揭示了TXA_2-TXA_2R系统在内毒素诱导和冷保存/再灌流肝损伤中的致病意义。冷保存再灌注性肝损伤的发病机制。我们发现肝脏冷保存过程中，肝巨噬细胞处于启动状态。结果表明，阻断肝巨噬细胞可抑制肝内鼻窦内凝血和白细胞黏附，从而抑制肝脏微循环障碍。Na~+/Ca~(2+)交换器在激活的Ito细胞中的表达我们首先证明了Na^/Ca^&gt；交换器是一种与肝纤维化相关的转运蛋白，它偶联Ca^&t；&gt；向相反方向的Na^转位，并有助于维持细胞内钙的动态平衡。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的基因Kan-1。通过与大鼠Kan-1基因探针的交叉杂交，我们从人肝cDNA文库中获得了一个克隆。这被发现与胆汁酸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.