| Project/Area Number |
14370350
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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 |
General surgery
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| Research Institution | Shinshu University |
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Principal Investigator |
HASHIKURA Yasuhiko Shinshu University, School of Medicine, Department of Surgery, Associate professor, 医学部, 助教授 (10228398)
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| Co-Investigator(Kenkyū-buntansha) |
URATA Koichi Shinshu University, Shinshu University Hospital, Operating Department, Assistant professor, 医学部附属病院・中央手術部, 助手 (70324267)
NAKAZAWA Yuichi Shinshu University, Shinshu University School of Medicine, Department of Surgery, Assistant professor, 医学部, 助手 (10273088)
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| Project Period (FY) |
2002 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2005: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2003: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2002: ¥3,600,000 (Direct Cost: ¥3,600,000)
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| Keywords | liver transplantation / ischemia-reperfusion injury / cytokine / apoptosis / ES cell / fulminant hepatic failure / MCI-186 / 肝血管構築 / 拒絶反応 / C型肝炎 |
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| Research Abstract |
1.Hepatic warm ischemia-reperfusion injury (IRI) during hepatectomy and liver transplantation is a major cause of liver dysfunction in which the pathologic role of free radicals is a major concern. To assess the effect of MCI-186 (edaravone) on hepatic IRI, male Wistar rats were subjected to partial hepatic ischemia for 60 min after pretreatment with vehicle (group C) or MCI-186 (group M). Group M showed significantly lower levels of serum alanine aminotransferase and hepatic lipid peroxidation than group C, and also significantly lower expression levels of mRNA for cytokines, chemokines and intercellular adhesion molecule-1. There were fewer tissue monocytes and neutrophils in group M than in group C. Our findings suggest that treatment with MCI-186 attenuates hepatic IRI in this rat in vivo model.
2.The mechanisms of Fas-Fas ligand (Fas-FasL)-mediated apoptosis in the pathogenesis of fulminant hepatic failure (FHF) have not been well defined. This clinical study was carried out to ass
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ess which cells expressed Fas-FasL and to determine their involvement. As the results, the numbers of TUNEL-, FasL-, and CD68-positive cells in the livers of patients with FHF were significantly larger than in those with CH or with normal livers. Double immunofluorescence staining showed that FasL was expressed predominantly on liver macrophages and rarely on CD8-positive lymphocytes. Macrophages and their expression of FasL may play roles in the pathogenesis of FHF.
3.We selected sublines with a high capability for differentiation to contracting cardiomyocytes and also produced germ-line chimeric mice from a parent ES line. We also succeed in establishing embryoid bodies prepared from the ES cells that differentiated into not only hepatocytes but also at least two mesodermal lineages : cardiomyocytes that supported liver development and endothelial cells corresponding to sinusoids. The expression of albumin was significantly higher in cardiomyocytes that had arisen in differentiated ES cells than in those that had not. Our in vitro system for liver organogenesis consists of a blood/sinusoid vascular-like network and hepatocyte layers and shows higher levels of hepatic function, such as albumin production and ammonia degradation, than hepatic cell lines and primary cultures of murine adult hepatocytes. This innovative system will lead to the development of second-generation regenerative medicine techniques using ES cells and is expected to be useful for the development of bioartificial liver systems and drug-metabolism assays. Less
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