The Novel Hemostatic and Tissue Protective Treatment Elucidating the Pathophysiology of Blast Lung Injury

• Project/Area Number: 25462843
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Emergency medicine
• Research Institution: National Defense Medical College
• Principal Investigator: HAGISAWA KOHSUKE 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究, 医学教育部医学科専門課程, 助教 (50539244)
• Co-Investigator(Kenkyū-buntansha): KINOSHITA Manabu 防衛医科大学校, 医学教育部医学科専門課程, 准教授 (70531391) ; SATOH Shunichi 防衛医科大学校, 防衛医学研究センター, 准教授 (90502906) ; SUZUKI Hidenori 日本医科大学, 医学部, 准教授 (30158977)
• Co-Investigator(Renkei-kenkyūsha): TAKEOKA Shinji 早稲田大学, 理工学術院, 教授 (20222094) ; SAITOH Daizoh 防衛医科大学校, 防衛医学研究センター, 教授 (90531632) ; HANDA Makoto 慶應義塾大学, 医学部, 教授 (40129614)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: Blast Lung Injury / 止血凝固作用 / アデノシン作用 / レーザー誘起衝撃波 / ドラッグデリバリシステム / アデノシン / 止血作用 / 血小板代替物 / 抗サイトカイン作用

Outline of Final Research Achievements

Fibrinogen gamma-chain (HHLGGAKQAGDV, H12)-coated, adenosine diphosphate-encapsulated liposomes [H12-(ADP)-liposomes] can accumulate at bleeding sites where they release ADP that is rapidly metabolized to adenosine, which has tissue-protective effects.
We investigated the efficacy of H12-(ADP)-liposomes to treat blast lung injury, with a focus on adenosine signaling. Pretreatment as well as post-treatment with H12-(ADP)-liposomes significantly increased mouse survivals and mitigated pulmonary tissue damage/hemorrhage and neutrophil accumulation after LISW exposure. Pretreatment with H12-(ADP)-liposomes reduced albumin and macrophage inflammatory protein-2 levels in bronchoalveolar lavage fluid. Although H12-(ADP)-liposome pretreatment did not affect blood coagulation activity in the injured mice, its beneficial effect on blast lung injury were significantly abrogated by adenosine receptor A2A or A2B antagonism, suggesting that adenosine signaling improved lung injury.

Research Products

• [Journal Article] Fibrinogen γ-Chain Peptide-Coated Adenosine 5' Diphosphate-Encapsulated Liposomes Rescue Mice From Lethal Blast Lung Injury via Adenosine Signaling. (2016)
  • Author(s): Hagisawa K, Miyawaki H, Kinoshita M, Miyazaki H, Yanagawa R, Doi M, Takeoka S, Suzuki H, Seki S, Saitoh D, Nishida Y, Handa M.
  • Journal Title: Critical Care Medicine Volume: 44 Issue: 9 Pages: e827-e837
  • DOI: 10.1097/ccm.0000000000001707
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Noradrenalin effectively rescues mice from blast lung injury caused by laser-induced shock waves. (2015)
  • Author(s): Miyawaki H, Saito D, Hagisawa K, Noguchi M, Sato S, Kinoshita M, Miyazaki H, Sato Y, Harada N, Sakamoto T.
  • Journal Title: Intensive Care Medicine Experimental Volume: 32 Issue: 1 Pages: 32-32
  • DOI: 10.1186/s40635-015-0069-7
  • Peer Reviewed / Open Access
• [Journal Article] Treatment with fibrinogen γ-chain peptide-coated, adenosine 5'-diphosphate-encapsulated liposomes as an infusible hemostatic agent against active liver bleeding in rabbits with acute thrombocytopenia (2015)
  • Author(s): Hagisawa K, Nishikawa K, Yanagawa R, Kinoshita M, Doi M, Suzuki H, Iwaya K, Saitoh D, Seki S, Takeoka S, Handa M, Nishida Y.
  • Journal Title: Transfusion. Volume: 55 Issue: 2 Pages: 314-325
  • DOI: 10.1111/trf.12829
  • Peer Reviewed
• [Journal Article] 衝撃波による致死的肺出血マウスに対する人工血小板（H12-ADP-liposome）の救命効果 (2014)
  • Author(s): 萩沢康介、木下学、宮脇博基、佐藤俊一、鈴木英紀、土井麻美、武岡真司、小野聡、斎藤大蔵、西田育弘
  • Journal Title: Shock （日本ショック学会雑誌） Volume: 29 Pages: 1-8
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] レーザー衝撃波による肺出血に対するH12-ADP-liposomeの救命効果 (2015)
  • Author(s): 萩沢康介、木下学、宮脇博基、佐藤俊一、鈴木英紀ら
  • Organizer: 第22回日本血液代替物学会 シンポジウム・人工血小板の新しい展開に向けて
  • Place of Presentation: 熊本
  • Year and Date: 2015-10-23
• [Presentation] FIBRINOGEN GAMMA-CHAIN PEPTIDE-COATED, ADP-ENCAPSULATED LIPOSOMES RESCUE MICE (2015)
  • Author(s): K. Hagisawa, M. Kinoshita, H. Miyawaki, H. Miyazaki
  • Organizer: 38TH ANNUAL CONFERENCE ON SHOCK
  • Place of Presentation: DENVER, COLORADO
  • Year and Date: 2015-06-06 – 2015-06-09
• [Presentation] Fibrinogen gamma-chain peptide-coated, Adenosine Diphosphate-encapsulated Liposomes Rescue Lethal Blast Lung Injury Hemorrhage via Purinergic Signaling. (2014)
  • Author(s): Hagisawa K, Kinoshita M, Miyawaki H
  • Organizer: American Heart Association 2014 Resuscitation Science Symposium, (Young Investigator Award受賞)
  • Place of Presentation: Chicago
  • Year and Date: 2014-11-15 – 2014-11-16
• [Presentation] 衝撃波による致死的肺出血マウスに対する人工血小板（H12-ADP-liposome）の救命効果 (2014)
  • Author(s): 2.萩沢康介、木下学、宮脇博基、佐藤俊一、鈴木英紀、土井麻美、武岡真司、小野聡、斎藤大蔵、西田育弘
  • Organizer: 第29回日本ショック学会 学会長賞受賞
  • Place of Presentation: 愛媛県松山市
  • Year and Date: 2014-05-17
• [Presentation] 衝撃波による致死的肺出血マウスに対する人工血小板（H12-ADP-liposome）の救命効果 (2014)
  • Author(s): 萩沢康介、木下学、宮脇博基ら
  • Organizer: 第29回日本Shock学会
  • Place of Presentation: 松山市
• [Presentation] H12-ADP-liposomeの新たな適応: 衝撃波による肺出血マウスに対するH12-ADP-liposomeの救命効果 (2013)
  • Author(s): 萩沢康介、木下学、宮脇博基ら
  • Organizer: 第20回日本血液代替物学会 シンポジウム人工血小板／H12-(ADP)リポソームの前臨床
  • Place of Presentation: 奈良市