| Project/Area Number |
16390376
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Kyoto University |
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Principal Investigator |
HATANO Etsuro (2005) Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (80359801)
嶌原 康行 (2004) 京都大学, 医学研究科, 助教授 (30196498)
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| Co-Investigator(Kenkyū-buntansha) |
KAWADA Norifumi Osaka City University, School of Nfedicine, Associate Professor, 医学部, 助教授 (30271191)
NAKAMURA Hajime Kyoto University, Translational Research Center, Associate Professor, 探索医療センター, 助教授 (70303914)
UYAMA Naoki Kyoto University, Graduate School of Medicine, 医学研究科, 医員 (70402873)
波多野 悦朗 京都大学, 医学研究科, 助手 (80359801)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥13,700,000 (Direct Cost: ¥13,700,000)
Fiscal Year 2005: ¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 2004: ¥7,100,000 (Direct Cost: ¥7,100,000)
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| Keywords | Hepatic stellate cells / thioredoxin / ROCK / Rho kinase inhibitor / ischemia / reperfusion injury / hepatic microcirculation / intravital microscopy / N-acetylcisteine / liver failure / NAC / 慢性肝炎 / 星細胞 / 術後肝障害 / 酸化ストレス / ROCK / Rho kinase阻害剤 / 肝細胞癌 / chemoprevention |
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| Research Abstract |
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-27632
Rock/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
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