Extracellular histones as a myocardial depressant factor

• Project/Area Number: 25670763
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Emergency medicine
• Research Institution: Kagoshima University
• Principal Investigator: ITO Takashi 鹿児島大学, 医歯(薬)学総合研究科, 特任講師 (20381171)
• Co-Investigator(Kenkyū-buntansha): MARUYAMA Ikuro 鹿児島大学, 大学院医歯学総合研究科, 特任教授 (20082282)
• Co-Investigator(Renkei-kenkyūsha): NAKAHARA Mayumi 鹿児島大学, 大学院医歯学総合研究科, 特任助教 (90707514) ; KAWAHARA Ko-ichi 大阪工業大学, 工学部生命工学科, 特任教授 (10381170)
• Research Collaborator: NAGASATO Tomoka 藤森工業株式会社 ; YAMADA Shingo 株式会社シノテスト
• Project Period (FY): 2013-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 敗血症 / 免疫学 / 病理学 / ヒストン

Research Abstract

Extracellular histone H3 was not detectable in plasma of healthy volunteers, but significant levels were observed in patients with sepsis and DIC. Histone injection caused cardiac damage in mice as evidenced by ST-segment depression in electrocardiogram, CK elevation in blood exam, and contractile dysfunction in echocardiogram. Recombinant thrombomodulin bound to extracellular histones, reduced histone-induced cardiac damage, and rescued mice from histone-induced death. These results suggest that extracellular histones might be a myocardial depressant factor in sepsis, and that recombinant thrombomodulin might be effective in neutralizing histone's toxicity.

Research Products

• [Journal Article] Toxic effects of extracellular histones and their neutralization by vitreous in retinal detachment (2014)
  • Author(s): Kawano H, Ito T, Yamada S, Hashiguchi T, Maruyama I, Hisatomi T, Nakamura M, Sakamoto T
  • Journal Title: Lab Invest Volume: 94(5) Pages: 569-85
  • Peer Reviewed
• [Journal Article] トロンボモジュリンの基礎 (2014)
  • Author(s): 伊藤隆史
  • Journal Title: 日本血栓止血学会誌 Volume: 25(1) Pages: 55-60
  • NAID: 130003393340
• [Journal Article] Toxic effects of extracellular histones and their neutralization by vitreous in retinal detachment. (2014)
  • Author(s): Kawano H, Ito T, Yamada S, Hashiguchi T, Maruyama I, Hisatomi T, Nakamura M, Sakamoto T.
  • Journal Title: Laboratory Investigations Volume: 94(5) Issue: 5 Pages: 569-585
  • DOI: 10.1038/labinvest.2014.46
  • Peer Reviewed / Open Access
• [Journal Article] Recombinant Thrombomodulin Protects Mice against Histone-Induced Lethal Thromboembolism (2013)
  • Author(s): Nakahara M, Ito T, Kawahara K, Yamamoto M, Nagasato T, Shrestha B, Yamada S, Miyauchi T, Higuchi K, Takenaka T, Yasuda T, Matsunaga A, Kakihana Y, Hashiguchi T, Kanmura Y, Maruyama I
  • Journal Title: PLoS One Volume: 8(9)
  • Peer Reviewed
• [Journal Article] Recombinant thrombomodulin protects mice against histone-induced lethal thromboembolism. (2013)
  • Author(s): Nakahara M, Ito T, et al.
  • Journal Title: PLoS One Volume: 8(9) Issue: 9 Pages: 75961-75961
  • DOI: 10.1371/journal.pone.0075961
  • Peer Reviewed
• [Presentation] 血栓と免疫、そして、その制御 (2014)
  • Author(s): 伊藤隆史
  • Organizer: 第41回日本集中治療医学会学術集会
  • Place of Presentation: 京都
• [Presentation] Massive thrombosis evoked by extracellular histones : Is it DIC? (2013)
  • Author(s): Takashi Ito, Mayumi Nakahara, and Ikuro Maruyama
  • Organizer: 59th Scientific and Standardization Committee Meeting of the ISTH 2013
  • Place of Presentation: オランダ.
• [Presentation] 炎症に起因する血栓症の病態解明～新規メディエーターとしてのPAMPs・DAMPs～ (2013)
  • Author(s): 伊藤隆史
  • Organizer: 第35回日本血栓止血学会学術集会
  • Place of Presentation: 山形