Hydrogen Perfusion & Inhalation in Liver Transplantation: When, Where, and How?

• Project/Area Number: 17H04271
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: Kyoto University
• Principal Investigator: Hata Koichiro 京都大学, 医学研究科, 准教授 (90523118)
• Co-Investigator(Kenkyū-buntansha): 上本 伸二 京都大学, 医学研究科, 教授 (40252449)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2019: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2017: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 水素 / 臓器保存 / 肝移植 / 虚血再灌流障害 / 単純冷保存 / HyFACS / 水素ガス / 臓器移植 / medical gas / gas biology / 抗酸化 / 虚血再灌流傷害 / 分子状水素 / HyFACS法 / 抗酸化作用 / 活性酸素種 / 体外治療 / ヒト心房性利尿ペプチド / 虚血再灌流 / 体外灌流法 / 活性酸素 / 抗酸化物質

Outline of Final Research Achievements

Molecular hydrogen (H2) has the remarkable potential to selectively neutralize harmful reactive oxygen species, just leaving harmless H2O. Towards its clinical application, however, there are multiple obstacles including flammability, high diffusivity/permeability, and low solubility. Thus we developed a simple ex vivo conditioning, HyFACS (Hydrogen Flush After Cold Storage), that involves injecting unsaturated H2 solution directly into the blood vessels of cold-stored organs just before implantation. Moreover, we tested the additive effect combined with HyIAR (Hydrogen Inhalation After Reperfusion), the most common method of H2 application.
HyFACS provides the additive protection to cold-stored livers, combined with HyIAR. HyFACS seems to be useful as a simple end-ischemic preconditioning for solid organ transplantation.

Academic Significance and Societal Importance of the Research Achievements

虚血再灌流障害（IRI）は固形臓器移植における宿命的課題である。IRIでは、虚血後の再酸素化による活性酸素種（ROS）の発生が種々の組織障害を惹起する。分子状水素（H2）には、組織障害性の強いROSを選択的に中和し、その最終産物は水であるという利点がある一方で、その臨床応用に向けては、可燃性、高拡散性/透過性、低溶解度など解決すべき複数の障壁がある。そこで我々は、H2の新たなDelivery SystemとしてHyFACS法を考案した。この新たな水素の応用法は “利点を生かし難点を減ずる”革新的なDDSであり、その保護効果、水素ガス吸入法との相加的保護効果を実証した。

Research Products

• [Journal Article] Bortezomib Against Refractory Antibody-Mediated Rejection After ABO-Incompatible Living-Donor Liver Transplantation (2019)
  • Author(s): Tajima Tetsuya、Hata Koichiro、Okajima Hideaki、Nishikori Momoko、Yasuchika Kentaro、Kusakabe Jiro、Yoshizawa Atsushi、Fukumitsu Ken、Anazawa Takayuki、Tanaka Hirokazu、Wada Seidai、Doi Junshi、Takaori-Kondo Akifumi、Uemoto Shinji
  • Journal Title: Transplantation Direct Volume: 5 Issue: 10 Pages: e491-e491
  • DOI: 10.1097/txd.0000000000000932
  • Peer Reviewed / Open Access
• [Journal Article] Human Atrial Natriuretic Peptide in Cold Storage of Donation After Circulatory Death Rat Livers: An Old but New Agent for Protecting Vascular Endothelia? (2019)
  • Author(s): Nigmet Y, Hata K, Tamaki I, Okamura Y, Tsuruyama T, Miyauchi H, Kusakabe J, Tajima T, Hirao H, Kubota T, Inamoto O, Yoshikawa J, Goto T, Tanaka H, Uemoto S.
  • Journal Title: Transplantation Volume: 103 Issue: 3 Pages: 512-521
  • DOI: 10.1097/tp.0000000000002552
  • Peer Reviewed
• [Journal Article] Bortezomib against refractory antibody-mediated rejection after ABO-incompatible living-donor liver transplantation: Dramatic effect in acute-phase? (2019)
  • Author(s): Tetsuya Tajima, Koichiro Hata, Hideaki Okajima, Momoko Nishikori, Kentaro Yasuchika, Jiro Kusakabe, Atsushi Yoshizawa, Ken Fukumitsu, Takayuki Anazawa, Hirokazu Tanaka, Seidai Wada, Junshi Doi, Akifumi Takaori-Kondo, and Shinji Uemoto
  • Journal Title: Transplant Direct Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] Hydrogen Flush After Cold Storage as a New End-Ischemic Ex Vivo Treatment for Liver Grafts Against Ischemia/Reperfusion Injury (2018)
  • Author(s): Tamaki Ichiro、Hata Koichiro、Okamura Yusuke、Nigmet Yermek、Hirao Hirofumi、Kubota Toyonari、Inamoto Osamu、Kusakabe Jiro、Goto Toru、Tajima Tetsuya、Yoshikawa Junichi、Tanaka Hirokazu、Tsuruyama Tatsuaki、Tolba Rene H.、Uemoto Shinji
  • Journal Title: Liver Transplantation Volume: 24 Issue: 11 Pages: 1589-1602
  • DOI: 10.1002/lt.25326
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of Donor Age on Recipient Survival in Adult-to-adult Living-donor Liver Transplantation. (2017)
  • Author(s): Kubota T, Hata K, Sozu T, Ueda Y, Hirao H, Okamura Y, Tamaki I, Yoshikawa J, Kusakabe J, Uemoto S, et al.
  • Journal Title: Annals of Surgery Volume: In Press Issue: 6 Pages: 1126-1133
  • DOI: 10.1097/sla.0000000000002194
  • Peer Reviewed
• [Journal Article] Reply to "Representing Subnormothermic Machine Perfusion in Fatty Livers: The Complete Picture?" (2017)
  • Author(s): Okamura Y, Hata K, Uemoto S.
  • Journal Title: American Journal of Transplantation Volume: In Press Issue: 5 Pages: 1423-1424
  • DOI: 10.1111/ajt.14254
  • Peer Reviewed / Open Access
• [Journal Article] Impact of Subnormothermic Machine Perfusion Preservation in Severely Steatotic Rat Livers: A Detailed Assessment in an Isolated Setting. (2017)
  • Author(s): Okamura Y, Hata K, Tanaka H, Hirao H, Kubota T, Inamoto O, Kageyama S, Tamaki I, Yermek N, Yoshikawa J, Uemoto S.
  • Journal Title: American Journal of Transplantation Volume: In Press Issue: 5 Pages: 1204-1215
  • DOI: 10.1111/ajt.14110
  • Peer Reviewed / Open Access
• [Journal Article] 3.境界グラフトの健常性維持と機能再生を目指した移植肝臓器保存戦略 (2017)
  • Author(s): 秦 浩一郎, 岡村 裕輔, 玉木 一路, 後藤 徹, Yermek Nigmet, 日下部 治郎, 吉川 潤一, 田嶋 哲也, 稲本 道, 久保田 豊成, 平尾 浩史, 影山 詔一, 田中 宏和, 上本 伸二
  • Journal Title: Organ Biology Volume: 24巻2号 Pages: 61-67
  • Peer Reviewed
• [Presentation] NOVEL APPLICATION OF MOLECULAR HYDROGEN IN ORGAN TRANSPLANTATION: HYDROGEN FLUSH AFTER COLD STORAGE (HYFACS) AND HYDROGEN INHALATION AFTER REPERFUSION (HYIAR) (2019)
  • Author(s): Tamaki Ichiro、Hata Koichiro、Okamura Yusuke、Nigmet Yermek、Hirao Hirofumi、Kubota Toyonari、Inamoto Osamu、Kusakabe Jiro、Goto Toru、Tajima Tetsuya、Yoshikawa Junichi、Tanaka Hirokazu、Tsuruyama Tatsuaki、Tolba Rene H.、Uemoto Shinji
  • Organizer: 19th Congress of the European Society for Organ Transplantation
  • Int'l Joint Research
• [Presentation] 臓器保存・移植領域への分子状水素の応用戦略 "利点を生かし、欠点を減ずるための創意工夫" (2019)
  • Author(s): 秦 浩一郎，玉木 一路, 田嶋 哲也, 日下部 治郎,宮内 英孝, 趙 向東, 岡村 裕輔，田中 宏和, 岡本 竜弥, 上本 伸二
  • Organizer: 第9回 日本分子状水素学会総会
• [Presentation] スポンサードシンポジウム① 水素ガスの虚血・再灌流障害軽減効果と臨床応用の展望： 「臓器移植領域における分子状水素の臨床応用に向けて ～利点を生かし、欠点を減らすための応用戦略～」 (2019)
  • Author(s): 秦 浩一郎，玉木 一路, 日下部 治郎, 田嶋 哲也, 宮内 英孝, 趙 向東, 岡村 裕輔，田中 宏和, 岡本 竜弥, 上本 伸二
  • Organizer: 第46回日本臓器保存生物医学会学術集会
  • Invited
• [Presentation] Human Atrial Natriuretic Peptide (hANP) in Cold Storage of Donation after Cardiac Death Livers: A New Tool for Protecting Vascular Endothelia? (2018)
  • Author(s): 3.Yermek Nigmet, Koichiro Hata, Yusuke Okamura, Ichiro Tamaki, Tatsuaki Tsuruyama, Hirofumi Hirao, Toyonari Kubota, Jiro Kusakabe, Junichi Yoshikawa, Toru Goto, Tetsuya Tajima, Hirokazu Tanaka, and Shinji Uemoto
  • Organizer: 2018 American Transplant Congress (ATC), Seattle, WA, June; 6th, 2018
  • Int'l Joint Research
• [Presentation] Hydrogen Flush after Cold Storage (HyFACS): A New, Simple, and Non-invasive Graft Reconditioning against Ischemia/Reperfusion Injury? (2018)
  • Author(s): 8.Ichiro Tamaki, Koichiro Hata, Yusuke Okamura, Yermek Nigmet, Hirofumi Hirao, Toyonari Kubota, Osamu Inamoto, Jiro Kusakabe, Junichi Yoshikawa, Toru Goto, Tetsuya Tajima, Hirokazu Tanaka, and Shinji Uemoto
  • Organizer: The 8th International Forum of Liver Surgery, Graz, Austria, May 26th-27th, 2018
  • Int'l Joint Research
• [Presentation] Bortezomib against Post-trasnplant Antibody-Mediated Rejection in ABO-incompatible Living-Donor Liver Transplantation: Report of a Successful Case. (2018)
  • Author(s): 9.Tetsuya Tajima, Koichiro Hata, Hideaki Okajima, Ichiro Tamaki, Nigmet Yermek, Jiro Kusakabe, Junichi Yoshikawa, Toru Goto, Hirokazu Tanaka, and Shinji Uemoto
  • Organizer: The 8th International Forum of Liver Surgery, Graz, Austria, May 26th-27th, 2018
  • Int'l Joint Research
• [Presentation] Prognostic index consisting of platelet count, total-bilirubin, and prothrombin time on postoperative day-14 precisely predict recipient mortality in adult-to-adult living-donor liver transplantation: A single-center analysis. (2018)
  • Author(s): 5.Jiro Kusakabe, Koichiro Hata, Hirokazu Tanaka, Yusuke Okamura, Ichiro Tamaki, Nigmet Yermek, Junichi Yoshikawa, Tetsuya Tajima, Toru Goto and Shinji Uemoto
  • Organizer: The 2018 Joint International Congress of ILTS, ELITA & LICAGE from May, 2018 in Lisbon, Portugal.
  • Int'l Joint Research
• [Presentation] Postoperative Thrombocytopenia (< 2 weeks) Determines the Fate of Adult LDLT: Proposal of “LTx-TMA”. (2017)
  • Author(s): Koichiro Hata, Hirokazu Tanaka, Kayoko Endo, Jiro Kusakabe, Ichiro Tamaki, Tetsuya Tajima, Toru Goto, Junichi Yoshikawa, Takashi Ito, Atsushi Yoshizawa, Shintaro Yagi, Hideaki Okajima, Toshimi Kaido, Akira Shimizu, and Shinji Uemoto.
  • Organizer: The 9th Meeting of 5 Asian LDLT Centers, 21st Oct. 2017, Kyoto, Japan.
  • Int'l Joint Research
• [Presentation] Hydrogen Perfusion after Cold Storage; A New, Simple, and Non-invasive Graft Conditioning for Ameliorating Hepatic Ischemia/Reperfusion Injury? (2017)
  • Author(s): Ichiro Tamaki, Koichiro Hata, Yusuke Okamura, Nigmet Yermek, Hirofumi Hirao, Toyonari Kubota, Osamu Inamoto, Jiro Kusakabe, Junichi Yoshikawa, Tetsuya Tajima, Toru Goto, and Shinji Uemoto.
  • Organizer: The 18th Congress of the European Society for Organ Transplantation (ESOT), 24-27 Sep. 2017, Barcelona, Spain.
  • Int'l Joint Research
• [Presentation] Hydrogen Perfusion after Cold Storage; A New, Simple, and Non-invasive Post-Conditioning for Ameliorating Hepatic Ischemia/Reperfusion Injury? (2017)
  • Author(s): Ichiro Tamaki, Koichiro Hata, Yusuke Okamura, Nigmet Yermek, Hirofumi Hirao, Toyonari Kubota, Osamu Inamoto, Jiro Kusakabe, Junichi Yoshikawa, Hirokazu Tanaka, Shoichi Kageyama, Tetsuya Tajima, Toru Goto, and Shinji Uemoto.
  • Organizer: The 52nd meeting of the European Society for Surgical Research (ESSR), 14-17 June 2017, Amsterdam, the Netherlands.
  • Int'l Joint Research
• [Presentation] Efficacy of the novel Preservation Solution, Ecosol, in a rat liver transplantation model. (2017)
  • Author(s): TANAKA Hirokazu, Doorschodt BMD, Fukushima FK, Assar AMAM, Kadaba Srinivasan, Pawlowsky KP, Hata KH, Tolba RT.
  • Organizer: The 52nd meeting of the European Society for Surgical Research (ESSR), 14-17 June 2017, Amsterdam, the Netherlands.
  • Int'l Joint Research
• [Presentation] V5 & V8 Reconstruction in Right-lobe Living-Donor Liver Transplantation; Our Standardized Procedures and Recent Modification of “half-circumferential anastomosis”. (2017)
  • Author(s): Koichiro Hata, Tetsuya Tajima, Takayuki Anazawa, Atsushi Yoshizawa, Shintaro Yagi, Hideaki Okajima, Toshimi Kaido, and Shinji Uemoto.
  • Organizer: The 6th Biennial Congress of the Asian-Pacific Hepato-Pancreato-Biliary Association, 7-10, June 2017, Yokohama, Japan.
  • Int'l Joint Research
• [Presentation] Postoperative Low Platelet Count and Elevated Total Bilirubin Impact the Mortality and Morbidity in Living-donor Liver Transplantation. (2017)
  • Author(s): Jiro Kusakabe, Koichiro Hata, Yusuke Okamura, Ichiro Tamaki, Nigmet Yermek, Junichi Yoshikawa, Tetsuya Tajima, Toru Goto, Hirokazu Tanaka, Hideaki Okajima, Toshimi Kaido, and Shinji Uemoto.
  • Organizer: 15th Congress of the Asian Society of Transplantation (CAST), 27-30 November 2017, Cebu, Philippines
  • Int'l Joint Research
• [Presentation] Bortezomib against Post-operative Antibody-Mediated Rejection in ABO-incompatible Living-Donor Liver Transplantation: Report of a Successful Case. (2017)
  • Author(s): Tetsuya Tajima, Koichiro Hata, Hideaki Okajima, Ken Fukumitsu, Atsushi Yoshizawa, Ichiro Tamaki, Nigmet Yermek, Jiro Kusakabe, Junichi Yoshikawa, Toru Goto and Shinji Uemoto
  • Organizer: 15th Congress of the Asian Society of Transplantation (CAST), 27-30 November 2017, Cebu, Philippines.
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 虚血再灌流の防御剤および臓器の処置方法 (2018)
  • Inventor(s): 秦浩一郎、玉木一路、岡村祐輔、上本伸二、平野伸一、佐藤文平
  • Industrial Property Rights Holder: 秦浩一郎、玉木一路、岡村祐輔、上本伸二、平野伸一、佐藤文平
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Acquisition Date: 2019
• [Patent(Industrial Property Rights)] 虚血再灌流障害の防御剤及び臓器の処置方法 (2018)
  • Inventor(s): 秦浩一郎、玉木一路、岡村祐輔、上本伸二
  • Industrial Property Rights Holder: 秦浩一郎、玉木一路、岡村祐輔、上本伸二
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Overseas
• [Patent(Industrial Property Rights)] 虚血再灌流障害の防御剤及び臓器の処置方法 (2017)
  • Inventor(s): 秦浩一郎、玉木一路、岡村祐輔、上本伸二、平野 伸一、佐藤 文平
  • Industrial Property Rights Holder: 京都大学、MiZ株式会社
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
  • Acquisition Date: 2019
• [Patent(Industrial Property Rights)] 虚血再灌流障害の防御剤及び臓器の処置方法 (2017)
  • Inventor(s): 秦浩一郎、玉木一路、岡村祐輔、上本伸二
  • Industrial Property Rights Holder: 秦浩一郎、玉木一路、岡村祐輔、上本伸二
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017