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

1)硫氧还蛋白在肝纤维化和星状细胞活化中的作用：硫氧还蛋白是一种具有抗氧化和抗细胞凋亡作用的小分子氧化还原活性蛋白。我们研究了硫氧还蛋白对肝纤维化的保护作用。在硫代乙酰胺诱导的大鼠肝纤维化模型中，肝细胞内源性硫氧还蛋白的诱导明显。过表达硫氧还蛋白可抑制肿瘤坏死因子α诱导的肝癌细胞死亡。与野生型小鼠相比，转基因小鼠抑制了硫代乙酰胺诱导的肝纤维化和丙二醛在肝脏中的积累。从转基因小鼠分离的肝星状细胞比从野生型小鼠分离的肝星状细胞的增殖能力低。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。硫氧还蛋白不能控制培养的星状细胞中胶原基因的表达。硫氧还蛋白有可能通过异烟肼…控制肝纤维化2)N-乙酰半胱氨酸(NAC)对慢性肝炎患者肝功能、肝癌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后应用NAC治疗6个月。观察肿瘤复发指标(AFP、PIVKA-II)、肝纤维化指标(P-III-P、IV型胶原)、谷草转氨酶(AST)、丙氨酸氨基转移酶(ALT)及血小板计数。2例患者肿瘤标志物数值有改善或无变化。2例患者肝纤维化指标均有改善。1例患者的AST、ALT和血小板计数均有改善。此外，我们还对2例肝切除术后高胆红素血症患者进行了NAC治疗。在1例患者中，肠内注射NAC后，血清胆红素水平下降。另一方面，NAC治疗并未改善另一位患者的血清胆红素水平。在这项研究中，我们不能清楚地证明NAC在控制肝功能和肝细胞癌复发以及治疗肝切除术后肝功能衰竭方面的有效性。3)肝脏微循环和Rock/Rho激酶抑制剂Y-27632Rock/Rho激酶抑制剂Y-27632也被认为可以防止肝星状细胞的激活和防止纤维化。在大鼠肝脏缺血再灌流模型上，我们用半侧肝钳夹方法对其进行了研究。活体显微镜观察显示，Y-27632通过明显改善肝脏微循环，对肝脏缺血/再灌注性损伤具有保护作用。与假手术组比较，肝窦及肝窦后小静脉直径、肝窦血流灌注率维持不变。血窦和血窦后小静脉内白细胞黏附较少，对血液流动障碍也有保护作用。Y-27632还能改善内毒素血症所致的微循环障碍。较少

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