| Project/Area Number |
17390427
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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 |
Anesthesiology/Resuscitation studies
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| Research Institution | Tottori University |
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Principal Investigator |
MINAMI Yukari Tottori University, University Hospital, Junior Associate Professor (10243403)
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| Co-Investigator(Kenkyū-buntansha) |
OKAZAKI Naoto Tottori University, Faculty of Medicine, Assistant Professor (30032204)
MATSURA Tatsuya Tottori University, Faculty of Medicine, Associate Professor (00199746)
MOCHIDA Shinsuke Tottori University, University Hospital, Assistant Professor (70403433)
ISHIBE Yuichi Tottori University, Emeritus Professor (40122014)
永井 小夜 鳥取大学, 医学部附属病院, 助手 (10294331)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥14,190,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2005: ¥10,200,000 (Direct Cost: ¥10,200,000)
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| Keywords | Heat shock protein / Acute organ damage / Geranylgeranylacetone / Lipopolysacch aride / Septic shock / Polaprezinc / Macrophage / Cytokine / 温熱刺激 / 熱ショック蛋白 / 急性臓器機能障害 |
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| Research Abstract |
The present study was performed to find new heat shock protein (HSP) inducers, which can prevent acute organ damages and can be used in the clinical field without serious side effects. Geranylgeranylacetone (GGA) is an anti-ulcer drug developed in Japan and known as a potent HSP inducer. Recently, we have found that oral administration of GGA to rats before lipopolysaccharide (LPS) injection induces HSP70 in several organs, inhibits production of proinflammatory cytokines and nitric oxide (NO), and prevents organ damages, resulting in improvement of survival rates. However, it is still unknown whether the inhibitory effect of GGA on the production of cytokines and NO in LPS-mediated endotoxin shock model involves the direct action to inflammatory mediator-producing cells such as macrophages. Therefore, we first investigated whether GGA inhibits LPS-induced macrophage activation, and whether the inhibition by GGA was related to HSP induction. We demonstrated that GGA inhibited the binding of LPS to the surface of macrophages, resulting in suppression of cytokine liberation and NO production regardless of its HSP-inducing activity. We next determined whether GGA protects mouse liver against acetaminophen (APAP)-induced injury and whether it has potential as a therapeutic agent for APAP overdose. In these experiments, GGA has been identified as a new antidote to APAP injury, acting by induction of HSP70. The potential of GGA as a therapeutic tool is strongly supported by its ability to inhibit hepatic injury even when administered after ingestion of APAP. Finally, we investigated whether another anti-ulcer drug polaprezinc (PZ), a chelate compound consisting of zinc and L-carnosine, can suppress mortality, pulmonary inflammation and plasma NO levels in endotoxin shock mice after LPS challenge. These experiments revealed that PZ, in particular its zinc subcomponent, inhibits LPS-induced endotoxin shock via anti-inflammatory activity.
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