Development of a new effective therapy of fulminant hepatitis to focus on sTLR.

• Project/Area Number: 24591888
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Keio University
• Principal Investigator: TANABE Minoru 慶應義塾大学, 医学部, 講師 (50197513)
• Co-Investigator(Kenkyū-buntansha): TANAKA Masayuki 慶應義塾大学, 医学部, 助教 (30573414) ; SHINODA Masahiro 慶應義塾大学, 医学部, 講師 (50286499) ; NISHIYAMA Ryo 慶應義塾大学, 医学部, 助教 (70528322) ; TAKAYANAGI Atsushi 慶應義塾大学, 医学部, 講師 (80245464)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: HMGB1 / sTLR / 遺伝子治療 / 劇症肝不全 / 体外循環 / 急性肝不全 / 肝細胞移植

Outline of Final Research Achievements

We paid attention to High-mobility group box1(HMGB1) and showed as an important mediator of fulminant hepatitis. We tried to make adenovirus vector which encoded amino acids of sTLR, the receptor of HMGB1. We couldn't make the adenovirus vector, but we suceeded in makeing adenovirus vector which encoded amino acids of HMGB1 Box-A protein known to act as a competitive inhibitor of HMGB1 and plasmid of sRAGE known as soluble Receptor for advanced glycation endproducts like HMGB1. Transfection these prodcts to rats of fulminant hepatitis showed decreased hepatic enzymes, plasma HMGB1, and histological findings and survival were improved.

Research Products

• [Journal Article] Gene transfer of high-mobility group box 1 box-A domain in a rat acute liver failure model (2015)
  • Author(s): Tanaka, M
  • Journal Title: Journal of Surgical Research Volume: 194 Issue: 2 Pages: 571-580
  • DOI: 10.1016/j.jss.2014.11.022
  • Peer Reviewed / Open Access
• [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] 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] Effect of an omega-3 lipid emulsion in reducing oxidative stress in a rat model of intestinal ischemia-reperfusion injury. (2012)
  • Author(s): Arisue A, Shimojima N, Tomiya M, Shimizu T, Harada D, Nakayama M, Tomita H, Shinoda M, Tanabe M, Maruyama I, Mizuno M, Kuroda T, Wakabayashi G, Morikawa Y.
  • Journal Title: Pediatr Surg Int. Volume: 28 Issue: 9 Pages: 913-918
  • DOI: 10.1007/s00383-012-3144-0
  • 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] Suppressive effects of Interleukin-18 on liver function in rat liver allografts (2012)
  • Author(s): Ono S
  • Journal Title: J Surg Res Volume: 176 Issue: 1 Pages: 293-300
  • DOI: 10.1016/j.jss.2011.07.053
  • Peer Reviewed
• [Journal Article] Alarmin (HMGB1) など―代表的Alarmin, HMGB1研究の今― (2012)
  • Author(s): 篠田昌宏
  • Journal Title: 日本外科感染症学会雑誌 Volume: 9 Pages: 335-341
• [Journal Article] Pharmacokinetics of mizoribine in adult living donor liver transplantation (2012)
  • Author(s): Shinoda M
  • Journal Title: Transplant Proc Volume: 44 Pages: 1329-1335
  • Peer Reviewed
• [Presentation] ブタ急性肝不全モデルにおけるHMGB1吸着療法の試み (2014)
  • Author(s): 雨宮隆介、篠田昌宏
  • Organizer: 外科侵襲とサイトカイン研究会
  • Place of Presentation: 徳島
  • Year and Date: 2014-12-13
• [Presentation] ブタ急性肝不全モデル・体外循環モデルの確立 (2014)
  • Author(s): 雨宮隆介、篠田昌宏
  • Organizer: 癌と炎症と抗酸化研究会
  • Place of Presentation: 大分
  • Year and Date: 2014-11-15
• [Presentation] ラット急性肝不全モデルにおけるHMGB1 A box遺伝子導入の病態改善効果 (2014)
  • Author(s): 雨宮隆介、篠田昌宏
  • Organizer: 消化器病学会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-23
• [Presentation] HMGB1に着目した急性肝不全の病態理解と治療法の開発 (2013)
  • Author(s): 篠田昌宏, 田中真之, 西山亮, 大島剛, 高野公徳, 海老沼浩利, 高柳淳, 山田晋吾, 宮庄拓, 須田康一, 林田哲, 八木洋, 阿部雄太, 日比泰造, 北郷実, 尾原秀明, 竹内裕也, 板野理, 丸山征郎, 田邉稔, 北川雄光
  • Organizer: 第39回日本急性肝不全研究会
  • Place of Presentation: 東京
• [Presentation] HMGB1に着目した急性肝不全の病態理解と体外循環吸着療法の可能性 (2013)
  • Author(s): 田中真之, 篠田昌宏, 西山亮, 高野公徳, 高柳淳, 丸山征郎, 田邉稔, 北川雄光
  • Organizer: 第49回日本移植学会総会
  • Place of Presentation: 京都
• [Presentation] HMGB1 A box domainの遺伝子導入方法の確立 (2013)
  • Author(s): 田中真之, 篠田昌宏, 高柳淳, 西山亮, 大島剛, 高野公徳, 山田晋吾, 宮庄拓, 須田康一, 林田哲, 八木洋, 阿部雄太, 日比泰造, 北郷実, 尾原秀明, 竹内裕也, 板野理, 丸山征郎, 田邉稔, 北川雄光
  • Organizer: 第40回日本臓器保存生物医学会学術集会
  • Place of Presentation: 東京
• [Presentation] ラット急性肝不全モデルにおけるHMGB1 A box遺伝子導入の効果 (2013)
  • Author(s): 雨宮隆介, 篠田昌宏, 田中真之, 高柳淳, 西山亮, 大島剛, 山田晋吾, 宮庄拓, 須田康一, 八木洋, 林田哲, 阿部雄太, 日比泰造, 北郷実, 尾原秀明, 竹内裕也, 板野理, 丸山征郎, 田邉稔, 北川雄光
  • Organizer: 第20回外科侵襲とサイトカイン研究会
  • Place of Presentation: 渋川
• [Presentation] 急性肝不全患者におけるHMGB1動態と動物モデルにおけるHMGB1制御の効果
  • Author(s): 篠田昌宏
  • Organizer: 第112回日本外科学会定期学術集会
  • Place of Presentation: 幕張
• [Presentation] HMGB1 A box遺伝子導入ベクターの樹立とラット急性肝不全モデルにおける予後改善効果
  • Author(s): 篠田昌宏
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 東京
• [Presentation] HMGB1阻害タンパクA boxの遺伝子導入ベクターの確立とラット急性肝不全モデルにおける予後改善効果
  • Author(s): 田中真之
  • Organizer: 第27回日本Shock学会総会
  • Place of Presentation: 東京
• [Presentation] Hemoadsorption of high-mobility group box 1 in swine acute liver failure model
  • Author(s): Shinoda M
  • Organizer: American Transplant Congress 2012
  • Place of Presentation: Boston
• [Presentation] ラット急性肝不全モデルにおけるHMGB1 A box domainの肝への遺伝子導入とその効果
  • Author(s): 田中真之
  • Organizer: 第38回日本急性肝不全研究会
  • Place of Presentation: 金沢
• [Presentation] ブタ急性肝不全モデルにおけるHigh mobility group box-1 吸着カラムの有用性の 検討
  • Author(s): 篠田昌宏
  • Organizer: 第30回日本肝移植研究会
  • Place of Presentation: 福岡
• [Presentation] Hemoadsorption of high-mobility group box 1 in swine acute liver failure mdoel
  • Author(s): Shinoda M
  • Organizer: 10th World Congress of the International Hepato-Pancreato-Biliary Association
  • Place of Presentation: Paris
• [Presentation] Gene transfer of the A box domain of high mobility group box 1 into the liver in rat acute liver failure model
  • Author(s): Shinoda M
  • Organizer: 10th World Congress of the International Hepato-Pancreato-Biliary Association
  • Place of Presentation: Paris
• [Presentation] 薬剤誘導性ラット劇症肝不全モデルの作成～DHLHISZnの病態改善効果検討へ向けて～
  • Author(s): 田中真之
  • Organizer: 第3回癌・炎症とαリポ酸研究会
  • Place of Presentation: 由布
• [Presentation] Gene transfer of A Box domain of High Mobility Group Box 1 in rat acute liver failure model
  • Author(s): Tanaka M
  • Organizer: The 63rd Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Boston
• [Presentation] Hemoadsorption of high-mobility group box 1 in a swine acute liver failure model
  • Author(s): Shinoda M
  • Organizer: The 63rd Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Boston
• [Presentation] HMGB1制御による急性肝不全に対する新治療の開発
  • Author(s): 篠田昌宏
  • Organizer: 第40回日本集中治療医学会学術集会
  • Place of Presentation: 松本
• [Presentation] 急性肝不全におけるHigh mobility group box-1吸着療法の基礎的検討
  • Author(s): 篠田昌宏
  • Organizer: 第49回日本腹部救急医学会総会
  • Place of Presentation: 福岡
• [Presentation] High mobility group box-1に着目した急性肝不全治療の基礎的検討
  • Author(s): 篠田昌宏
  • Organizer: 第99回日本消化器病学会総会
  • Place of Presentation: 鹿児島