Extension of limitation on hepatic warm ischemia, with special reference to analysis of the microcirculatory disturbance and the mechanism of ischemic tolerance from the view points of stress responce protein
| Project/Area Number |
09671300
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Mie University |
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Principal Investigator |
NOGUCHI Takashi Mie University, Faculty of Medicine, Professor, 医学部, 教授 (40144258)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1999: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1998: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1997: ¥600,000 (Direct Cost: ¥600,000)
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| Keywords | ischemic preconditioning / heat shock protein / sublethal ischemia / pharmacological inducer stress protein / Geranyl-geranyl-acetone / nuclear transcription factor / nitric oxide / apotosis / 微小循環障害 / 類洞内皮細胞機能 / 小腸虚血モデル / cytoprotection / 肝虚血耐性 / 生体顕微鏡 / 動的解析 / Hsp inducer / Geranylgeranylacetone / 初回虚血 / 再虚血 / 肝細胞障害 / 内皮細胞障害 / 監視機構 |
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| Research Abstract |
<Purpose> This study was performed to investigate the cytoprotective effect of ischemic tolerance established by initial transient ischemia as a sub lethal stress or administration of Geranyl-geranyl-acetone (GGA),which are known to be one of heat shock protein (Hsp) inducers, make an extension of hepatic warm ischemia limit, and to evaluate the mechanism ischemic tolerance, hepatic microcirculation and endothelial cell function with in vivo to in vitro. Moreover, small intestinal model was evaluated as well as hepatic model.
<Materials & Methods> Male wistar rats were subjected to 45 min of hepatic ischemia followed reperfusion : (1) 20 min liver ischemia 7 days prior to 45 min ischemia, or (2) oral administration of GGA 200 mg/kgBW for 7 or 14 days prior to 45 min ischemia. Examined were survival rate, liver function, hepatic tissue blood flow, histologic findings, expression of Hsp 70 and NF-kB (Western blot), and NOィイD22ィエD2 + NOィイD23ィエD2 concentration in isolated hepatocyte/non-par
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enchymal cell cultures 8Griess method). In intestinal models which were subjected to 90 min superior mesenteric artery clumped, preconditioning groups were (1) 30 min initial ischemia 7 days prior to 90 min ischemia and (2) oral administration of GGA 14 days prior to 90 min ischemia.
<Results> 1. The 7-day survival rate : all animals of 45 min ischemia were died within 48 hrs after reperfusion, in contrast, preconditioning groups were significantly higher (83% and 75%) respectively. 2. In preconditioning groups, ALT & HA levels in the serum, hepatic blood flow, and histologic findings including increased apoptosis in hepatocytes and endothelial cells showed a significant improvement . 3. Hsp 70 induction was remarkably increased immediately after reperfusion to 6 hrs. 4. The expression and activation of NF-kB were significantly suppressed. 5. The NO production was inhibited by iNOS in preconditioning groups. 6. Intestinal ischemia limit was extended by preconditioning and apoptosis was regulated with increased Hsp 70 expression.
<Conclusion> Ishemic preconditioning and oral administration of GGA protected liver sinusoidal endothelial cell dysfunction and improved the hepatic microcirculatory disturbance in the postischemic liver by inducing Hsp 70. This Hsp 70 suppresses NF-kB to regulate the overproduction of NO attribute to iNOS. Preconditioning by ischemia or drugs establishes ischemic tolerance in small intestine as well as liver. Therefore, performing the ischemic preconditioning is expected to be of much benefit to extend hepatectomy, or liver transplantation and so on. Less
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Report
(4 results)
Research Products
(9 results)
