| Project/Area Number |
12307025
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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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 | Keio University |
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Principal Investigator |
KITAJIMA Masaki Department of Surgery, Keio University School of Medicine, Professor, 医学部, 教授 (90112672)
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| Co-Investigator(Kenkyū-buntansha) |
WAKABAYASHI Go Department of Surgery, Keio University School of Medicine, Assistant Professor, 医学部, 講師 (50175064)
SHIMAZU Motohide Department of Surgery, Keio University School of Medicine, Assistant Professor, 医学部, 講師 (70124948)
KOYASU Shigeo Department of Immunology, Keio University School of Medicine, Professor, 医学部, 教授 (90153684)
TANABE Minoru Department of Surgery, Keio University School of Medicine, Teaching Staff, 医学部, 助手 (50197513)
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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 |
¥37,890,000 (Direct Cost: ¥34,500,000、Indirect Cost: ¥3,390,000)
Fiscal Year 2001: ¥14,690,000 (Direct Cost: ¥11,300,000、Indirect Cost: ¥3,390,000)
Fiscal Year 2000: ¥23,200,000 (Direct Cost: ¥23,200,000)
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| Keywords | small bowel transplantation / ischemia-reperfusion injury / mitogen activated protein kinase (MAPK) / interleukin-1 (IL-1) / tumor necrosis factor-α (INF-α) / apoptosis / 虚血再灌流障害 / interleukin-1(IL-1) / 免疫抑制療法 / MAP kinase |
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| Research Abstract |
Because small intestine is one of the most susceptible organs to ischemia, ischemia-reperfusion injury is formidably limiting factor in small intestinal transplantation. By using rat small intestinal ischemia-reperfusion injury model, we demonstrated that TNF-α and IL-1β is produced in the rat small intesyinal ischemia-reperfusion injury and that the production can be reduced by the specific TNF-α and IL-1β inhibitor, attenuating the intestinal injury. Recently, mitogen-activated protein kinase (MARK) superfamily has been widely noticed as upupstream signal transduction mechanisms for TNF-α and IL-1β have been reported. Especially, c-Jun N-terminal kinase (JNK) and p38 induce cell apoptosis by various stimuli including ischemia. In addition, p38 acts as a key enzyme to produce IL-1 and TNF, suggesting these enzymes play a key role in ischemia-reperfusion Injury. In the present study, we investigated the pathophysiologic significance of JNK and p38 in rat small intestinal ischemia-reperfusion injury. Remarkable activation of JNK and p38 was shown in the injured small intestinal tissue after ischemia-reperfusion by using kinase assay. Immunohistochemistry of the intestinal tissue after reperfusion revealed that the activated p38 was mainly located in the epithelial cells of the villus tip, where TUNNEL positive apoptotic cells were present. Administration of LL-Z1640-2, a dual inhibitor of JNK and p38, effectively suppressed the activation of these enzymes, and reduced the number of apoptotic cells on villus tip, resulting that the mucosal morphology was well preserved. These results indicate that JNK and p38 play a key role in small intestinal ischemia-reperfusion injury, and that the simultaneous inhibition of these enzymes may provide a novel therapeutic approach to overcome ischemic damage in small intestinal transplantation.
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