Study on the improvement of liver injury by controlling sinusoidal cells and spleen

1)肝脏冷保存与再灌注损伤采用Tunel法和电镜观察大鼠肝脏冷保存与再灌注过程中肝脏细胞凋亡的变化。因此，我们发现凋亡只发生在高发生率的窦内皮细胞（SECs）中，导致窦壁脱离。这种现象在冷保存后再灌注中明显发现，但在单独冷保存中没有发现。血管内皮生长因子（VEGF）是一种具有生存和增殖功能的分子，可抑制细胞凋亡。此外，我们发现冷藏的脂肪肝的SEC非常脆弱，随着冷藏时间的延长，肝细胞内脂肪滴的大小变得更大。冷保存脂肪肝的这些变化似乎是脂肪肝中经常发生的无功能移植物的主要原因之一。我们证明肝细胞生长因子（HGF）改善了SECs的损伤并抑制了脂肪滴的增大。此外，我们发现在低温保存过程中，各种基因的表达发生了变化。2)通过抑制肝星状细胞活化改善肝硬化。我们之前报道了小G蛋白Rho的效应分子P160ROCK的抑制剂Y-27632抑制了肝星状细胞的活化，该化合物抑制了ccl4诱导的大鼠肝纤维化向肝硬化的发展。在本研究中，我们发现Y-27632改善了上述模型中已经建立的肝硬化，且无明显的副作用。这一结果可能是治疗肝硬化的一个有希望的策略。

1). Cold preservation and reperfusion injury of the liverApoptotic change in the liver was studied with Tunel method and electron microscopy in the cold preservation and reperfusion of the rat liver. Consequently, we found that apoptosis was occurred exclusively in the sinusoidal endothelial cells (SECs) with high incidence, leading to the detachment from the sinusoidal wall. This phenomenon was detected markedly in the cold preservation followed by reperfusion, but not in the cold preservation alone. Apoptosis in this experimental model was suppressed by vascular endothelial growth factor (VEGF) which has been well known to function as surviving and proliferative molecule. Furthermore, we showed that SEC of the fatty liver with cold storage was quite fragile and the size of the intra hepatocytic fatty droplet became larger in size as the cold preservation time was longer. These changes in the cold preserved fatty liver appeared to be one of the major causes of non-functioning graft which is frequently occurred in the fatty liver. We demonstrated that hepatocyte growth factor (HGF) ameliorated the impairment of SECs and inhibited enlargement of the fatty droplet. In addition, we showed that expressions of various kinds of the genes were changed during the cold preservation.2) Improvement of the liver cirrhosis by inhibition of activation of hepatic stellate cells. Previously, we reported that Y-27632, inhibitor of P160ROCK which is an effctor molecule of small G protein Rho, suppressed an activation of hepatic stellate cells, and that this compound inhibited the development into the liver cirrhosis in the CCL4-induced liver fibrosis of the rat. In the present study, we showed that Y-27632 ameliorated the already-established liver cirrhosis in the above-mentioned model without apparent side effects. This result may be a promising strategy for the liver cirrhosis.