The mechanism of worsening effects of benzodiazepine on immune defense

• Project/Area Number: 16K10958
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Anesthesiology
• Research Institution: Kindai University (2018); Osaka University (2016-2017)
• Principal Investigator: OHTA Noriyuki 近畿大学, 医学部, 准教授 (60379162)
• Co-Investigator(Kenkyū-buntansha): 藤野 裕士 大阪大学, 医学系研究科, 教授 (50252672)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥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)
• 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

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.

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

Research Products

• [Journal Article] Midazolam suppresses the lipopolysaccharide-stimulated immune responses of human macrophages via translocator protein signaling. (2019)
  • Author(s): 堀口祐、大田典之、山本俊介、古出萌、藤野裕士
  • Journal Title: International Immunopharmacology Volume: 66 Pages: 373-382
  • DOI: 10.1016/j.intimp.2018.11.050
  • Peer Reviewed
• [Journal Article] Haloperidol Suppresses NF-kappaB to Inhibit Lipopolysaccharide-Induced Pro-Inflammatory Response in RAW 264 Cells. (2016)
  • Author(s): Yamamoto S, Ohta N, Matsumoto A, Horiguchi Y, Koide M, Fujino Y
  • Journal Title: Med Sci Monit. Volume: 22 Pages: 367-72
  • Peer Reviewed
• [Presentation] TSPOリガンドEtifoxineによる炎症疾患の制御の可能性 (2018)
  • Author(s): 堀口祐、大田典之、山本俊介、古出萌、藤野裕士
  • Organizer: 日本麻酔科学会学術集会
• [Presentation] 集中治療におけるせん妄の発生と対策 (2017)
  • Author(s): 大田典之
  • Organizer: 日本麻酔科学会
  • Place of Presentation: 神戸
  • Year and Date: 2017-06-08
  • Invited
• [Presentation] Midazolam Suppresses Immune Response of Lipopolysaccharide-stimulated Macrophages Via TSPO Signaling (2017)
  • Author(s): Noriyuki Ohta
  • Organizer: American society of anesthesiologist
  • Int'l Joint Research
• [Book] 臨床麻酔 (2016)
  • Author(s): 大田典之
  • Total Pages: 8
  • Publisher: 新興交易医（株）出版部