Cellular mechanism in thrombin mediated HMGB1 release. Effect of cluster formation of HMGB1 on the cell-surface receptors.

• Project/Area Number: 23390412
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Emergency medicine
• Research Institution: Kagoshima University
• Principal Investigator: MARUYAMA Ikuro 鹿児島大学, 医歯(薬)学総合研究科, 特任教授 (20082282)
• Co-Investigator(Kenkyū-buntansha): KAWAHARA Koichi 大阪工業大学, 工学部生命工学科, 特任教授 (10381170) ; ITO Takashi 鹿児島大学, 大学院・医歯学総合研究科, 特任講師 (20381171) ; OYAMA Yoko 鹿児島大学, 大学院・医歯学総合研究科, 特任助教 (20583470) ; HASHIGUCHI Teruto 鹿児島大学, 大学院・医歯学総合研究科, 教授 (70250917)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2013: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2012: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2011: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
• Keywords: PAMPｓ / DAMPｓ / HMGB1 / inflammasome / トロンビン / PAR-1 / NF-ｋB / TLR-2 / TLR-4 / シグナル伝達 / 蛋白質 / 糖尿病 / 発現制御

Research Abstract

HMGB1, a representative danger associated molecular patterns, DAMP is released from almost all nucleated necrotic cells and activated epithelial cells including endothelial cells. The HMGB1 released out of the cells acts on Toll Like receptors(TLR)-2,TLR-4 and receptor for advanced glycation endproducts, RAGE. If the cells were primed by preceding PAMPs, pathogen associated molecular patterns, dual signalings from PAMPs and DAMPs generate and secrete IL-1b(beta) and IL-18 resulting self-defensive inflammation and hemostatic reaction. However excessive this dual signaling often reads to systemic and/or fulminant inflammation and coagulation resulting systemic inflammatory response syndrome(SIRS) and/or disseminated intravascular coagulation(DIC). We could present that for example HMGB1 and LPS or thrombin may have a crucial role in these severe conditions. Thus the regulation and intervention of PAMPs and DAMPs are important in preventive medicine in the emergency medicines.

Research Products

• [Journal Article] Comparative evaluation of direct thrombin and factor Xa inhibitors with antiplatelet agents under flow and static conditions : an in vitro flow chamber model (2014)
  • Author(s): Hosokawa K, Ohnishi T, Sameshima H, Miura N, Koide T, Maruyama I, Tanaka KA
  • Journal Title: PLoS One Volume: 9(1) Issue: 1 Pages: 86491-86491
  • DOI: 10.1371/journal.pone.0086491
  • Peer Reviewed
• [Journal Article] Antithrombotic effects of PAR1 and PAR4 antagonists evaluated under flow and static conditions (2014)
  • Author(s): Hosokawa K, Ohnishi T, Miura N, Sameshima H, Koide T, Tanaka KA, Maruyama I
  • Journal Title: Thromb Res Volume: 133(1) Issue: 1 Pages: 66-72
  • DOI: 10.1016/j.thromres.2013.10.037
  • Peer Reviewed
• [Journal Article] Hemoadsorption of high-mobility group box chromosomal protein 1 using a column for large animals (2013)
  • Author(s): Nishiyama R, Shinoda M, Tanabe M, Oshima G, Takano K, Miyasho T, Fuchimoto Y, Yamada S, Inoue T, Shimada K, Suda K, Tanaka M, Hayashida T, Yagi H, Kitago M, Obara H, Itano O, Takeuchi H, Kawachi S, Maruyama I, Kitagawa Y
  • Journal Title: Eur Surg Res Volume: 51(3-4) Issue: 3-4 Pages: 181-90
  • DOI: 10.1159/000357563
  • Peer Reviewed / Open Access
• [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
• [Journal Article] Coagulation activity and white thrombus formation in the microminipig (2013)
  • Author(s): Miura N, Kawaguchi H, Nagasato T, Yamada T, Ito T, Izumi H, Sameshima H, Miyoshi N, Tanimoto A, Maruyama I
  • Journal Title: In Vivo Volume: 27(3) Pages: 357-61
  • Peer Reviewed
• [Journal Article] Analysing responses to aspirin and clopidogrel by measuring platelet thrombus formation under arterial flow conditions (2013)
  • Author(s): Hosokawa K, Ohnishi T, Sameshima H, Miura N, Ito T, Koide T, Maruyama I
  • Journal Title: Thromb Haemost Volume: 109(1) Issue: 01 Pages: 102-11
  • DOI: 10.1160/th12-06-0441
  • Peer Reviewed
• [Journal Article] Neutrophil elastase inhibitor improves survival rate after ischemia reperfusion injury caused by supravisceral aortic clamping in rats (2013)
  • Author(s): Fujimura N, Obara H, Suda K, Takeuchi H, Miyasho T, Kawasako K, Du W, Yamada S, Ono S, Matsumoto K, Matsuda S, Yagi H, Kitago M, Shinoda M, Itano O, Tanabe M, Sakamoto M, Maruyama I, Kitagawa Y
  • Journal Title: J Surg Res Volume: 180(1) Issue: 1 Pages: 31-36
  • DOI: 10.1016/j.jss.2012.04.037
  • Peer Reviewed
• [Journal Article] Immunohistochemical expression of thrombomodulin in vestibular schwannoma (2013)
  • Author(s): Yamahata H, Yunoue S, Tokimura H, Hanaya R, Hirano H, Tokudome M, Karki P, Yonezawa H, Sugata S, Kawahara K, Maruyama I, Arita K
  • Journal Title: Brain Tumor Pathol Volume: 30(1) Issue: 1 Pages: 28-33
  • DOI: 10.1007/s10014-012-0095-z
  • Peer Reviewed
• [Journal Article] Coagulation activity and white thrombus formation in the microminipig (2013)
  • Author(s): Miura N
  • Journal Title: In Vivo. Volume: 27(3) Pages: 357-61
  • Peer Reviewed
• [Journal Article] Neutrophil elastase inhibitor improves survival rate after ischemia reperfusion injury caused by supravisceral aortic clamping in rats. (2013)
  • Author(s): Fujimura N
  • Journal Title: J Surg Res. Volume: 180
  • Peer Reviewed
• [Journal Article] Immunohistochemical expression of thrombomodulin in vestibular schwanoma (2013)
  • Author(s): Yamahata, H.
  • Journal Title: Brain Tumor Pathol Volume: 30 Pages: 28-33
• [Journal Article] Paucity of CD34-positive cells and increased expression of high-mobility group box 1 in coronary thrombus with type 2 diabetes mellitus. (2012)
  • Author(s): Yamashita A, Nishihira K, Matsuura Y, Ito T, Kawahara K, Hatakeyama K, Hashiguchi T, Maruyama I, Yagi H, Matsumoto M, Fujimura Y, Kitamura K, Shibata Y, Asada Y.
  • Journal Title: Atherosclerosis. Volume: 224 Issue: 2 Pages: 511-514
  • DOI: 10.1016/j.atherosclerosis.2012.07.027
  • Peer Reviewed
• [Journal Article] Increased plasma levels of high mobility group box 1 in patients with acute liver failure (2012)
  • Author(s): Oshima G, Shinoda M, Tanabe M, Ebinuma H, Nishiyama R, Takano K, Yamada S, Miyasho T, Masugi Y, Matsuda S, Suda K, Fukunaga K, Matsubara K, Hibi T, Yagi H, Hayashida T, Yamagishi Y, Obara H, Itano O, Takeuchi H, Kawachi S, Saito H, Hibi T, Maruyama I, Kitagawa Y
  • Journal Title: Eur Surg Res Volume: 48(3) Issue: 3 Pages: 154-62
  • DOI: 10.1159/000338363
  • Peer Reviewed
• [Journal Article] Role of high mobility group box chromosomal protein 1 in ischemia-reperfusion injury in the rat small intestine (2012)
  • Author(s): Kojima M, Tanabe M, Shinoda M, Yamada S, Miyasho T, Suda K, Hibi T, Obara H, Itano O, Kawachi S, Kitajima M, Maruyama I, Kitagawa Y
  • Journal Title: J Surg Res Volume: 178(1) Issue: 1 Pages: 466-71
  • DOI: 10.1016/j.jss.2012.01.044
  • Peer Reviewed
• [Journal Article] Circulating high-mobility group box 1 and cardiovascular mortality in unstable angina and non-ST-segment elevation myocardial infarction (2012)
  • Author(s): Hashimoto T, Ishii J, Kitagawa F, Yamada S, Hattori K, Okumura M, Naruse H, Motoyama S, Matsui S, Tanaka I, Izawa H, Maruyama I, Nomura M, Ozaki Y
  • Journal Title: Atherosclerosis Volume: 221(2) Issue: 2 Pages: 490-5
  • DOI: 10.1016/j.atherosclerosis.2012.01.040
  • Peer Reviewed
• [Journal Article] Prediction of the neurological outcome with intrathecal high mobility group box 1 and S100B in cardiac arrest victims : a pilot study (2012)
  • Author(s): Oda Y, Tsuruta R, Fujita M, Kaneda K, Kawamura Y, Izumi T, Kasaoka S, Maruyama I, Maekawa T
  • Journal Title: Resuscitation Volume: 83(8) Issue: 8 Pages: 1006-12
  • DOI: 10.1016/j.resuscitation.2012.01.030
  • Peer Reviewed
• [Journal Article] Mitigation of occult lung injury by pneumonectomy via minithoracotomy in mice (2012)
  • Author(s): Kohno M, Watanabe M, Izumi Y, Tasaka S, Kitagawa Y, Maruyama I, Kobayashi K
  • Journal Title: Thorac Cardiovasc Surg Volume: 60(2) Issue: 02 Pages: 124-30
  • DOI: 10.1055/s-0030-1271011
  • Peer Reviewed
• [Journal Article] Paucity of CD34-positive cells and increased expression of high-mobility group box 1 in coronary thrombus with type 2 diabetes mellitus. (2012)
  • Author(s): Yamashita, A.
  • Journal Title: Atherosclerosis. Volume: 224 Pages: 511-514
  • Peer Reviewed
• [Journal Article] Increased plasma levels of high mobility group box 1 in patients with acute liver failure. (2012)
  • Author(s): Oshima G
  • Journal Title: Eur Surg Res Volume: 48 Pages: 154-62
  • Peer Reviewed
• [Journal Article] Circulating high-mobility group box a and cardiovascular mortality in unstable angina and non-ST-segment elevation myocardial infarction (2012)
  • Author(s): Hashimoto,T
  • Journal Title: Atherosclerosis Volume: 221 Pages: 490-495
  • Peer Reviewed
• [Journal Article] Role of high mobility group box chromosomal protein 1 in ischemia-reperfusion injury in the rat small intestine (2012)
  • Author(s): Kojima M, Maruyama I, Kitagawa Y, et al
  • Journal Title: J Surg Res Volume: (in press)
  • Peer Reviewed
• [Journal Article] Circulating high-mobility group box 1 and cardiovascular mortality in unstable angina and non-ST-segment elevation myocardial infarction (2012)
  • Author(s): Hashimoto T, Maruyama I, Ozaki Y., et al
  • Journal Title: Atherosclerosis Volume: 221 Pages: 490-5
  • Peer Reviewed
• [Journal Article] Prediction of the neurological outcome with intrathecal high mobility group box 1 and S100B in cardiac arrest victims : A pilot study (2012)
  • Author(s): Oda Y Maruyama I, Maekawa T, et al
  • Journal Title: Resuscitation Volume: (in press)
  • Peer Reviewed
• [Journal Article] 新規DIC 治療薬トロンボモジュリン製剤の作用機序 (2011)
  • Author(s): 伊藤隆史, 丸山征郎
  • Journal Title: 臨床血液 Volume: 52巻 Pages: 356-360
  • NAID: 130004501537
• [Journal Article] Gradual increase of high mobility group protein B 1 (HMGB1) in the lungs after the onset of acute exacerbation of idiopathic pulmonary fibrosis (2011)
  • Author(s): Ebina M, Taniguchi H, Miyasho T, Yamada S, Shibata N, Ohta H, Hisata S, Hirota N, Nishimura H, Ishizaka A, Maruyama I, Takashi K, Nukiwa T
  • Journal Title: Pulmonary Med Volume: 916486 Pages: 1-9
  • DOI: 10.1155/2011/916486
  • NAID: 120003072907
  • Peer Reviewed
• [Journal Article] Valproic acid increases susceptibility to endotoxin shock through enhanced release of HMGB1 (2011)
  • Author(s): Sugiura, et al
  • Journal Title: Shock Volume: 36(5) Issue: 5 Pages: 494-500
  • DOI: 10.1097/shk.0b013e31822f7e58
  • Peer Reviewed
• [Journal Article] Thrombomodulin : protectorate God of the vasculature in thrombosis and inflammation (2011)
  • Author(s): Ito T, Maruyama I
  • Journal Title: J Thromb Haemost Volume: Suppl 1 Pages: 168-73
  • DOI: 10.1111/j.1538-7836.2011.04319.x
  • Peer Reviewed
• [Journal Article] Valproic acid increases susceptibility to endotoxin shock through enhanced release o f high-mobility group box 1 (2011)
  • Author(s): Sugiura S, Maruyama I, Matsushita K., et al
  • Journal Title: Shock Volume: 36(5) Pages: 494-500
  • Peer Reviewed
• [Journal Article] Thrombomodulin : protectorate God of the vasculature in thrombosis and inflammation. J (2011)
  • Author(s): Ito T, Maruyama I
  • Journal Title: Thromb Haemost Volume: 9 Pages: 168-73
  • Peer Reviewed
• [Journal Article] Gradual increase of high mobility group protein b1 in the lungs after the onset of acute exacerbation of idiopathic pulmonary fibrosis (2011)
  • Author(s): Ebina M, Maruyama I, Nukiwa T, et al
  • Journal Title: Pulm Med Volume: 2011 Pages: 916486-916486
  • NAID: 120005761658
  • Peer Reviewed
• [Journal Article] Mitigation of occult lung injury by pneumonectomy via minithoracotomy in mice (2011)
  • Author(s): Kohno M, Maruyama I, Kobayashi K., et al
  • Journal Title: Thorac Cardiovasc Surg Volume: 60 Pages: 124-30
  • Peer Reviewed
• [Presentation] Regulation of Danger Signals from HMGB1and Histones by Endothelial or Circulating Thrombomodulin (2013)
  • Author(s): Ikuro Maruyama
  • Organizer: The Merinoff World Congress 2013 : HMGB1
  • Place of Presentation: Manhasset, NY
• [Presentation] Assay method of des-HMGB1, N-terminus cleaved out HMGB1 by thrombinthrombomodulin, and its clinical significance (2013)
  • Author(s): Ikuro Maruyama, Takashi Ito, Yoshio Azuma, Mayumi Nakahara, Teruto Hashiguchi, Shingo Yamada
  • Organizer: XXIVcongress of the ISTH
  • Place of Presentation: Amsterdam, The Netherlands