| Project/Area Number |
12470258
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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 |
YAMAMOTO Yuzo Kyoto University, Graduate school of Medicine, Lecturer, 医学研究科, 講師 (70281730)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAOKA Yoshio Kyoto University, Graduate Schoool of Medicine, Professor, 医学研究科, 教授 (90089102)
飯室 勇二 京都大学, 医学研究科, 助手 (30252018)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥15,800,000 (Direct Cost: ¥15,800,000)
Fiscal Year 2001: ¥6,900,000 (Direct Cost: ¥6,900,000)
Fiscal Year 2000: ¥8,900,000 (Direct Cost: ¥8,900,000)
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| Keywords | Preconditioning / molecular Chaperone / NF-kB / AP-1 / Ischemic tolerance of the liver / Liver ischemia / Reperfusion injury / signal pathway / 熱ショック前処置 / 肝虚血再灌流障害 / NF-kB / 炎症反応 / アポトーシス / 虚血再灌流障害 / 熱ショック蛋白 / NF-κB |
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| Research Abstract |
In order to elucidate the mechanism in the suppression of ischemia reperfusion injury by heat shock preconditioning, effect of heat shock preconditioning on the transcription factors which are activated upon ischemia-reperfusion of the liver and on the signal pathways along which transcriptional factors are activated was investigated. In addition, expressions of the genes that are regulated by these transcriptional genes above were also examined. Activation of NF-kB was significantly suppressed in the group of heat shock preconditioning although NF-kB was markedly activated after ischemia and reperfusion in the control group. It was revealed that this suppression of NF-kB activation by heat shock preconditioning was connected with the reduction of IKK-mdependent I-kB degradation during reperfusion period. Furthermore, it was suggested that molecular chaperone, HSP72, participated in this reduction of I-kB degradation. As the result that NF-kB activation was suppressed, expression of mRNA for proinflammatory mediators like iNOS, TNF-a and MIP-2 ; serum TNF-a level ; CINC level in the serum as well as liver tissue ; and neutrophil infiltration were significantly decreased in the group of heat shock preconditioning. On the other hand, another transcription factor, AP- 1, was activated rapidly after ischemia-reperfusion of the liver in the heat shock preconditioning group. Concomitantly with this activation, hemeoxygenase-1 was expressed. Interestigly, apoptosis of the hepatocytes was well suppressed although AP-1 activation is considered to induce apoptosis in vitro. This result of suppressed apoptosis in this vivo model seems to be the consequence of maintained hepatic microcirculation due to reduced inflanimatory reactions during early reperfusion period.
Heat shock preconditioning effectively modified the signal transduction pathways during ischemia-reperfusion of the liver and seemed to be an important mechanism to confer an ischemic tolerance.
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