| Project/Area Number |
16K10958
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Anesthesiology
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| Research Institution | Kindai University (2018)
Osaka University (2016-2017) |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
藤野 裕士 大阪大学, 医学系研究科, 教授 (50252672)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | ベンゾジアゼピン / TSPO / GABA / サイトカイン / ミダゾラム / CD86 / siRNA / 樹状細胞 / 接触過敏症 / ハプテン / リンパ球 / 副刺激分子 / インターロイキン12 / 遺伝子欠損マウス |
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| Outline of Final Research Achievements |
We examined the immunomodulatory effects of the benzodiazepine midazolam on human macrophages and associated molecular mechanisms. We analyzed effects of midazolam pretreatment on LPS-induced upregulation of the costimulatory molecule and the pro-inflammatory factors in THP-1 and in PMDMs. The effects of midazolam on NF-κB, and MAPK activation were analyzed in THP-1 cells. The role of TSPO was investigated using THP-1 cells overexpressing TSPO and with TSPO knockdown through transfection with small interfering RNA for TSPO.
Results Midazolam suppressed upregulation of CD80 and release of IL-6 and NO in THP-1 cells and PMDMs. Midazolam suppressed the activation of NF-κB/AP-1 and MAPKs in human THP-1 cells. Macrophages overexpressing TSPO exhibited enhanced susceptibility to immunosuppression by midazolam, and macrophages lacking TSPO expression exhibited reduced effects of midazolam. Midazolam inhibits LPS-stimulated immune responses in human macrophages by activating TSPO signaling.
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| Academic Significance and Societal Importance of the Research Achievements |
ベンゾジアゼピン系薬物は鎮静薬、麻酔薬として広く使用されている。近年ベンゾジアゼピンの使用がICUのなかに限らず、一般患者の感染症の予後に影響を与える可能性が示されてきた。この根底に潜むメカニズムについては様々なし探されてきたが分子論的な検討は少なかった。私たちの本検討はベンゾジアゼピン系薬物の免疫抑制メカニズムの一部を明らかにしたものとして価値が高いと考える
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