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

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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.