| Project/Area Number |
13672401
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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 Medic University, School of Medicine, Instructor, 医学部, 助手 (50075496)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2002: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2001: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | endotoxin / lipid A analog / vascular permeability / cytokine / nitric oxide (NO) / septic shock / endotoxin tolerance / glucocorticoid / 敗血症性ショック / 誘導型NO合成酵素(iNOS) / iNOS欠損マウス / プロスタグランジン |
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| Research Abstract |
Subcutaneous injection of lipopolysaccharide (LPS) increases plasma leakage in mouse skin. Pretreatment with LPS conditions mice tolerant to the LPS-induced plasma leakage. Nitric oxide (NO) has been suggested to be involved in these LPS effects. A specific role of inducible NO synthase (iNOS) was investigated in the LPS-induced plasma leakage using iNOS deficient mice. It has been postulated that most biological activities of LPS are derived from lipid A moiety. We examined the effect of lipid A analog (ONO-4007) in increasing plasma leakage. Subcutaneous injection of LPS in mice that were preinjected I.v. with Pontamine sky blue dye produced a dose-related increase in dye leakage in both iNOS deficient and wild-type mice with about 40% less dye leakage in iNOS deficient mice. The LPS-induced dye leakage was not inhibited by inhibitors of NOS and LPS pretreatment in iNOS deficient mice. These studies indicate that LPS-induced dye leakage is mediated by NO produced by iNOS, prostaglandin (PG), histamine and TNF-α. The tolerance against LPS-induced vascular permeability change may be mediated by iNOS induction. Subcutaneous injection of ONO-4007 induced a dose-dependent increase in dye leakage. In iNOS deficient mice, ONO-4007 increased the dye leakage. A constitutive NOS-derived NO, TNF-α and IL-1α but not PG or histamine play a role in ONO-4007-induced increase in plasma leakage. Although ONO-4007 mimics LPS in increasing vascular permeability, mechanisms of permeability change elicited by ONO-4007 were not identical to those of LPS. ONO-4007 induced transient tolerance to plasma leakage elicited by LPS, ONO-4007 and inflammatory mediators. Endogenous corticosterone, at least in part, plays a role in development of tolerance. The tolerance induced by LPS may provide a potential basis for the treatment of sepsis, lipid A analog may be useful as a prophylactic therapy of septic shock.
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