| Project/Area Number |
15590467
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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 |
Applied pharmacology
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| Research Institution | OKAYAMA UNIVERSITY |
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Principal Investigator |
TAKAHASHI Hideo Okayama Univ., Grad.Sch.of Med.and Dent., Res.Assis., 大学院・医歯学総合研究科, 助手 (60335627)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIBORI Masahiro Okayama Univ., Grad.Sch.of Med.and Dent., Prof., 大学院・医歯学総合研究科, 教授 (50135943)
MORI Shuji Okayama Univ., Grad.Sch.of Med.and Dent., Assist.Prof., 大学院・医歯学総合研究科, 助教授 (50220009)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | histamine / H2-receptors / hepatic injury / knockout mice / IL-18 / Lipopolysaccharide / Propionibacterium acnes / Kupffer cells / macrophages / 肝炎治療 / HDC / 細胞間シグナル伝達 / アポトーシス |
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| Research Abstract |
Inducible histamine and histamine H2-receptors have been suggested to be involved in innate immune response. We examined a functional role of inducible histamine in the protection against hepatic injury and lethality in Propionibacterium acnes-primed and lipopolysaccharide-induced hepatitis, using wistidine decarboxylase knockout and H2-receptor knockout mice. Lipopolysaccharide challenge after Propionibacterium acnes-priming increased histidine decar boxylase activity in the liver of wild-type mice, associated with a marked elevation of histamine turnover. Histidine decarboxylase-like immunoreactivity was observed in CD68-positive Kupffer cells/macrophages. Treatment of wild-type mice with famotidine or ranitidine but not d-chlorpheniramine augmented hepatic injury and inhibited the survival rate significantly. The same dose of Propionibacterium acnes and lipopolysaccharide induced severe hepatitis and high lethality in histidine decarboxylase knockout and H2-receptor knockout mice, the former were rescued by the subcutaneous injection of histamine. Immunohistochemical study supported the protective role of histamine against the apoptosis of hepatocytes. Histamine suppressed the expression of IL-18 and tumor necrosis factor-α in the liver, leading to the reduced plasma levels of cytokines including IL-18,TNF-α,IL-12,IFN-γ and IL-6. These findings as a whole indicated that endogenously produced histamine in Kupffer cells/macrophages plays a very important role in preventing excessive innate immune response in endotoxin-induced fulminant hepatitis through the stimulation of H2-receptors.
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