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

通过肝星状细胞的调节改善 HCC 肝切除术后的围手术期和术后管理。

基本信息

批准号：
16390376
负责人：
HATANO Etsuro
金额：
$ 8.77万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

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

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的氧化还原活性蛋白，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。硫代乙酰胺诱导的大鼠肝纤维化的肝细胞内源性硫氧还蛋白的诱导是明显的。硫氧还蛋白的过度表达抑制肿瘤坏死因子-α诱导的 HepG2 细胞死亡。与野生型小鼠相比，转基因小鼠中硫代乙酰胺诱导的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从野生型小鼠中分离的肝星状细胞。重组硫氧还蛋白在血清或PDGF-BB刺激下显着抑制原代培养的星状细胞的DNA合成。硫氧还蛋白无法控制培养的星状细胞中的胶原蛋白基因表达。硫氧还蛋白有潜力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和 HCC 复发以及肝切除术后肝功能衰竭的影响：NAC 已对 3 名慢性肝炎患者进行了 6 次治疗 HCC 肝切除术后数月。检测肿瘤复发标志物（AFP、PIVKA-II）、肝纤维化标志物（P-III-P、IV型胶原）、AST、ALT数值以及血小板数量。两名患者的肿瘤标志物数值有所改善或没有变化。 2 名患者的纤维化标志物得到改善。 1 名患者的 AST、ALT 和血小板数量有所改善。此外，我们还对 2 名肝切除后出现高胆红素血症的患者进行了 NAC 治疗。一名患者肠内给予 NAC 后血清胆红素水平下降。另一方面，NAC 给药并没有改善另一名患者的血清胆红素水平。在这项研究中，我们无法清楚地证明 NAC 对肝功能管理、HCC 复发以及肝切除术后肝衰竭的疗效证据。需要进行额外的评估。3) 肝脏微循环和 Rock/Rho 激酶抑制剂 Y-27632 Rock/Rho 激酶抑制剂 Y-27632 也可防止肝星状细胞活化并防止纤维化。我们使用肝脏半侧钳在大鼠肝脏缺血/再灌注模型中对其进行了研究。通过活体显微镜观察到，Y-27632 通过显着改善肝脏微循环来保护缺血/再灌注引起的肝脏损伤。与假手术组相比，血窦和窦后微静脉的直径、血窦灌注率保持不变。血窦和窦后微静脉中白细胞的粘附要少得多，这也导致血流紊乱的保护。 Y-27632 还表现出改善内毒素血症引起的微循环障碍的作用。较少的

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cytoprotective Effects of Geranylgeranylacetone against Retinal Photooxidative Damage

DOI：
10.1523/jneurosci.4866-04.2005
发表时间：
2005-03
期刊：
The Journal of Neuroscience
影响因子：
0
作者：
M. Tanito;Yongwon Kwon;N. Kondo;J. Bai;H. Masutani;Hajime Nakamura;J. Fujii;A. Ohira;J. Yodoi
通讯作者：
M. Tanito;Yongwon Kwon;N. Kondo;J. Bai;H. Masutani;Hajime Nakamura;J. Fujii;A. Ohira;J. Yodoi

Helicobacter felis-induced gastritis was suppressed in mice overexpressing thioredoxin-1