2015 Fiscal Year Research-status Report
敗血症性心筋の炎症制御と陽性変力作用改善を目的とした創薬基盤形成
| Project/Area Number |
15K15661
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| Research Institution | Nagoya University |
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Principal Investigator |
松田 直之 名古屋大学, 医学(系)研究科(研究院), 教授 (50332466)
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| Co-Investigator(Kenkyū-buntansha) |
服部 裕一 富山大学, 大学院医学薬学研究部(医学), 教授 (50156361)
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| Project Period (FY) |
2015-04-01 – 2017-03-31
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| Keywords | 敗血症 / 心筋細胞 / リボシメンダン / 陽性変力作用 |
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| Outline of Annual Research Achievements |
BALB/c mice and mouse macrophage cell line RAW264.7 cells. When levosimendan was continuously administered to cecal ligation and puncture model;induced septic mice, a significant improvement of left ventricular function was found without any change in heart rate, and hypotension was significantly mitigated. Furthermore, levosimendan conferred substantial protection against sepsis-associated inflammation in mice, as indicated by reduced lung injury and decreased blood proinflammatory and chemotactic cytokine levels. These beneficial effects of levosimendan led to a significant improvement of survival in mice after cecal ligation and puncture. In endotoxin-stimulated RAW264.7 macrophages, treatment with levosimendan and pimobendan suppressed overproduction of proinflammatory and chemotactic cytokines. Levosimendan and pimobendan were without effect on activation of the nuclear factor-kB, mitogen-activated protein kinase, and Akt pathways. Instead, levosimendan and pimobendan prevented high mobility group box 1 release from the nucleus to the extracellular space in macrophages. This was associated with inhibition of the Rho kinase signaling pathway. The elevated serum high mobility group box 1 levels in cecal ligation and puncture induced septic mice were also inhibited by continued administration of levosimendan and pimobendan. We suggest that the pharmacological profiles of levosimendan as both an inotrope and an anti-inflammatory agent could contribute to its clinical benefit in patients with sepsis with heart problems.
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
2施設共同研究として，順調に研究が進行している。
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| Strategy for Future Research Activity |
敗血症モデルマウスの心臓を摘出し，RT-PCR法，Western Blot法，および免疫組織染色法で，DAMPs受容体と下流の細胞内情報伝達系について，発現細胞と発現量を比較検討する。特に，IRAK-1，IRAK-M，TAK1，およびFADDの発現を解析し，抑制的遺伝子治療を考案する。また，心臓に発現する繊維芽細胞の変化を，敗血症モデルマウスで評価する。
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[Journal Article] Anti-Inflammatory Profile of Levosimendan in Cecal Ligation-Induced Septic Mice and in Lipopolysaccharide-Stimulated Macrophages.2015
Author(s)
Wang Q, Yokoo H, Takashina M, Sakata K, Ohashi W, Abedelzaher LA, Imaizumi T, Sakamoto T, Hattori K, Matsuda N, Hattori Y.
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Journal Title
Crit Care Med
Volume: 43
Pages: e508-20
DOI
Peer Reviewed / Acknowledgement Compliant
