| Project/Area Number |
16K11403
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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 |
Emergency medicine
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| Research Institution | Hyogo Medical University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | 好中球細胞外トラップ / アンチトロンビン / 敗血症 / 臓器障害 / エンドトキシン / 自然免疫 / 好中球 / NETs / アポトーシス |
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| Outline of Final Research Achievements |
Administration of AT III after the onset of endotoxemia improved outcomes in a mouse model. AT III treatment attenuated several changes induced in the lungs by endotoxemia including cxcl-2 mRNA expression, HMGB-1 protein expression, neutrophil accumulation, alveolar septal thickening, and NET formation. In cultures of neutrophils from healthy volunteers, lipopolysaccharide (LPS)-induced NET formation was significantly decreased by AT III treatment. A subset of cultures (7/22, 32%) generated few NETs in response to LPS stimulation, and AT III did not decrease NET formation in these cultures. AT III treatment tended to decrease NET formation by cultured neutrophils from septic patients. The protein expression of protein kinase C (PKC)α, but not PKCζ, was increased by AT III treatment. Treatment of the cultures with PKC inhibitors blocked the effects of AT III on NET formation.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究はATIIIの投与が過剰なNETs形成を抑制し臓器障害を抑制する可能性を示した。また、感染制御が確立していない状態での早期のATIII投与は、必要なNETs産生を抑制し、生体免疫にとって不利となるが、LPSによるNETs形成が不十分な検体にはATIIIの抑制作用が認められなかったことから、感染防御反応と過剰免疫の境界が不明瞭な病態においても有用なツールとなる可能性があると考えられた。敗血症患者におけるATIII投与は播種性血管内凝固（DIC）治療を主眼としているが、本研究成果より、ATIIIの抗炎症効果にNETs抑制も存在し、NETs由来臓器障害の抑制に効果的である可能性が示唆された。
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