| Project/Area Number |
09672336
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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 |
応用薬理学・医療系薬学
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| Research Institution | Tokyo Women's Medical University |
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Principal Investigator |
FUJII Emiko Tokyo Women's Medical University, School of Medicine, Associate Professor, 医学部, 助教授 (20075493)
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| Co-Investigator(Kenkyū-buntansha) |
IRIE Kaoru Tokyo Women's Medical University, School of Medicine, Instructor, 医学部, 助手 (50075496)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1998: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1997: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Keywords | vascular permeability / endotoxin tolerance / glucocorticoid / cytokine / nitric oxide / サイトカイン / 一酸化窒素 / プロスタグランジン |
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| Research Abstract |
Subcutaneous injection of endotoxin (LPS) and some inflammatory mediators to mice increases the dye leakage at the site of injection indicating the increased dermal microvascular permeability. We investigated whether desensitization develops to the increase in permeability elicited by LPS or inflammatory mediators after systemic administration of a single low-dose LPS in male mice. Plasma extravasation was determined by Pontamine sky blue leakage at the site of the skin where LPS and mediators were injected s.c. The dye leakage *duced by LPS, 5-hydroxytryptamine (5-HT), platelet-activating factor, substance P or histamine was significantly decreased by 60-80% in LPS-primed mice, which indicates the development of homologous and heterologous tolerance. Pretreatment with tumor necrosis factor (TNF)-alpha and interleukin (IL)-lalpha but not IL-6 induced the tolerance to LPS, and anti-TNF-alpha antibody and anti-IL-1alpha antibody reversed the LPS-induced tolerance. Homologous tolerance disappeared in the adrenalectomized mice. When mice were pretreated with both LPS and N^G-nitro-L-arginine methyl ester, a nitric oxide (NO) synthase inhibitor, the hyporesponsiveness to LPS and 5-HT disappeared. These results suggest that endogenous cytokines, glucocorticoids and NO may play a role for development of LPS-induced tolerance in microcirculation. The tolerance induced by LPS may provide a potential basis for the treatment of septic shock.
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