Improvement of perioperative and postoperative management after hepatic resection for HCC by the regulation of hepatic stellate cells.

1)硫氧还蛋白参与肝纤维化和星状细胞活化：硫氧还蛋白是一种小氧化还原活性蛋白，具有抗氧化和抗凋亡作用。我们研究了硫氧还蛋白对肝纤维化的保护作用。内源性硫氧还蛋白在硫乙酰胺诱导的大鼠纤维化肝细胞中有明显的诱导作用。过表达硫氧还蛋白可抑制肿瘤坏死因子-α-诱导的HepG2细胞死亡。与野生型小鼠相比，转基因小鼠的硫代乙酰胺诱导的肝纤维化和丙二醛在肝脏中的积累受到抑制。从转基因小鼠中分离的肝星状细胞的增殖能力低于野生型小鼠。重组硫氧还蛋白显著抑制血清或PDGF-BB刺激下原代培养的星状细胞DNA合成。硫氧还蛋白对培养的星状细胞胶原蛋白基因的表达没有抑制作用。硫氧还蛋白有可能通过抑制肝细胞死亡、星状细胞增殖和氧化应激来控制肝纤维化。2) NAC （n -乙酰半胱氨酸）对慢性肝炎患者肝功能、HCC复发及肝切除术后肝功能衰竭的影响：3例慢性肝炎患者肝切除术后给予NAC治疗6个月。观察肿瘤复发标志物（AFP、PIVKA-II）、肝纤维化标志物（P-III-P、IV型胶原）、谷丙转氨酶（AST）、谷丙转氨酶（ALT）、血小板数量。2例患者肿瘤标志物指标改善或不变。2例患者纤维化指标改善。1例患者谷丙转氨酶、谷丙转氨酶及血小板数改善。此外，我们对2例肝切除术后高胆红素血症患者给予NAC。在1例患者中，经肠内给药NAC后血清胆红素水平下降。另一方面，NAC给药没有改善另一名患者的血清胆红素水平。在本研究中，我们不能明确地证明NAC对肝功能和HCC复发的治疗以及肝切除术后肝功能衰竭的疗效。进一步的评估将是必要的。3)肝脏微循环和Rock/Rho激酶抑制剂，Y-27632Rock/Rho激酶抑制剂，Y-27632也被认为是防止肝星状细胞活化和防止纤维化。采用肝半侧夹持法对大鼠肝脏缺血再灌注模型进行了研究。活体显微镜观察，Y-27632通过显著改善肝脏微循环，保护肝脏缺血再灌注损伤。与假手术组比较，维持大鼠窦内静脉直径、窦后小静脉直径及窦内灌注率。白细胞在窦状静脉和窦后小静脉的粘附少得多，这也保护了血流的紊乱。Y-27632还能改善内毒素血症引起的微循环紊乱。少

1)The involvement of thioredoxin on liver fibrosis and stellate cells activation :Thioredoxin is a small redox-active protein with anti-oxidant and anti-apoptotic effect. We have investigated the protective effect of thioredoxin for hepatic fibrosis. Induction of endogenous thioredoxin was obvious in hepatocytes of thioacetamide-induced fibrotic liver of rats. Overexpression of thioredoxin inhibited tumor necrosis factor-α-induced death of HepG2 cells. Thioacetamide-induced fibrosis and accumulation of malondialdehyde in the liver was suppressed in transgenic mice as compared with wild-type mice. Hepatic stellate cells isolated from transgenic mice was less proliferative than those isolated from wild type mice. Recombinant thioredoxin significantly inhibited DNA synthesis of primary-cultured stellate cells under serum or PDGF-BB stimulation. Thioredoxin failed to control collagen gene expression in cultured stellate cells. Thioredoxin has a potential to control hepatic fibrosis via inh … More ibiting hepatocyte death, proliferation of stellate cells and oxidative stress.2 )Effect of NAC (N-acetylcisteine) on hepatic function and HCC recurrence of patients with chronic hepatitis and on postoperative liver failure after hepatic resection :NAC had been administered to 3 patients with chronic hepatitis for 6 months after hepatic resection for HCC. Markers for tumor recurrence(AFP, PIVKA-II) and liver fibrosis(P-III-P, type IV collagen), figures of AST and ALT, and the number of platelets were investigated. In two patients, figures of tumor markers were improved or unchanged. Markers of fibrosis were improved in 2 patients. Figures of AST, ALT and the number of platelets were improved in 1 patient.In addition, we had administered NAC to 2 post-hepatectomized patients with hyperbilirubinemia. In one patient, serum bilirubin level decreased after enteral administration of NAC. On the other hand, NAC administration did not improve serum bilirubin level of the other patient. In this research, we can not clearly show the evidence of efficacy of NAC on management of hepatic function and HCC recurrence and on postoperative liver failure after hepatic resection. Additional evaluation will be necessary.3)Hepatic microcirculation and Rock/Rho kinase inhibitor, Y-27632Rock/Rho kinase inhibitor, Y-27632 is also known to prevent activation of hepatic stellate cell and prevent fibrosis. We have investigated it in ischemia/reperfusion model of rat liver using hemi-lateral clamp of the liver. Y-27632 protected ischemia/reperfusion-induced injury of the liver through remarkable improvement of hepatic microcirculation, which was observed by intravital microscopy. Diamiter of sinusoid and postsinusoidal venule, sinusoidal perfusion rate were maintained as compared to sham group. Adherence of leucocytes in the sinusoid and postsinusoidal venule was much less, which results also in protection of disturbance of the blood flow. Y-27632 also exhibited to improve disturbance of microcirculation due to endotoxemia. Less