Hirahashi, Junichi

写真a

Affiliation

School of Medicine, Center for General Medicine Education Department of General Medicine Education Keio University School of Medicine (Shinanomachi)

Position

Assistant Professor/Senior Assistant Professor

Career 【 Display / hide

  • 1997.04
    -
    2000.12

    慶應義塾大学医学部腎臓内科助手

  • 2001.01
    -
    2002.01

    Harvard大学医学部BWH内科学腎臓部門ポスドク (Dr. Vicki Kelley Lab)

  • 2002.02
    -
    2004.06

    Harvard大学医学部BWH病理学血管研究部門ポスドク(Dr. Tanya Mayadas Lab)

  • 2004.07
    -
    2007.06

    東京大学医学部附属病院腎臓内分泌内科 助手

  • 2007.07
    -
    2014.01

    東京大学医学部附属病院腎臓内分泌内科 助教, 2012.5-2013.12 医局長

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Academic Background 【 Display / hide

  • 1993

    慶應義塾大学, 医学部

    University, Graduated

  • 1997

    慶應義塾大学, 医学部, 医学科

    Graduate School, Graduated, Doctoral course

Academic Degrees 【 Display / hide

  • 博士(医学), 慶應義塾大学, 1997

Licenses and Qualifications 【 Display / hide

  • 医師免許, 1993

  • 日本内科学会 認定内科医, 1999.09

  • 日本内科学会 総合内科専門医, 2006.12

  • 日本腎臓学会 腎臓専門医, 2008.04

  • 日本透析医学会 透析専門医, 2014.04

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Matters concerning Career Achievements 【 Display / hide

  • 2011.10
    -
    Present

    医療系大学間教養試験実施評価機構 OSCE評価者認定

     View Details

    第11-01-01-0027

  • 2015.08

    第20回 慶應義塾大学病院臨床研修指導医養成ワー クショップ 修了

     View Details

    第27-55号

  • 2019.08

    第24回 慶應義塾大学病院臨床研修指導医養成ワークショップタスクフォース

  • 2020.11

    プログラム責任者養成講習会修了 第5041号

  • 2020.11

    令和2年度プログラム責任者養成講習会 修了

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Research Areas 【 Display / hide

  • Life Science / Immunology (NETs, AAV)

  • Life Science / Nephrology (AKI, RPGN)

  • Life Science / Pharmaceutical chemistry and drug development sciences (創薬、構造活性相関研究)

Research Keywords 【 Display / hide

  • ANCA-associated vasculitis

  • IgA nephropathy

  • lactoferrin

  • NETs

  • AKI

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Research Themes 【 Display / hide

  • 糖尿病における心血管系疾患への脆弱性のメカニズムの解明と予防・治療法の開発, 

    2019.04
    -
    Present

  • 血小板ー白血球コンタクトの免疫学的解析による炎症メカニズムの解明と新規治療の開発, 

    2018.04
    -
    2021.03

  • 炎症性疾患におけるImmunothrombosisの制御異常と新たな治療法 の開発, 

    2015.04
    -
    2017.03

  • Neutrophil extracellular traps (NETs) and Immunothrombosis in inflammatory diseases, 

    2012
    -
    Present

  • Aspirin and Eicosapentaenoic Acid May Arrest Progressive IgA Nephropathy: A Potential Alternative to Immunosuppression, 

    2010
    -
    Present

 

Papers 【 Display / hide

  • Macrophage extracellular trap formation promoted by platelet activation is a key mediator of rhabdomyolysis-induced acute kidney injury

    Okubo, Koshu, Kurosawa, Miho, Kamiya, Mako, Urano, Yasuteru, Suzuki, Akari, Yamamoto, Kazuhiko, Hase, Koji, Homma, Koichiro, Sasaki, Junichi, Miyauchi, Hiroaki, Hoshino, Tatsuo, Hayashi, Matsuhiko, Mayadas, Tanya N., Hirahashi, Junichi

    NATURE MEDICINE (Nature Medicine)  24 ( 2 ) 232 - + 2018.03

    Research paper (scientific journal), Last author, Corresponding author, Accepted,  ISSN  1078-8956

     View Summary

    Rhabdomyolysis is a serious syndrome caused by skeletal muscle injury and the subsequent release of breakdown products from damaged muscle cells into systemic circulation. The muscle damage most often results from strenuous exercise, muscle hypoxia, medications, or drug abuse and can lead to life-threatening complications, such as acute kidney injury (AKI). Rhabdomyolysis and the AKI complication can also occur during crush syndrome, an emergency condition that commonly occurs in victims of natural disasters, such as earthquakes, and man-made disasters, such as wars and terrorism. Myoglobin released from damaged muscle is believed to trigger renal dysfunction in this form of AKI. Recently, macrophages were implicated in the disease pathogenesis of rhabdomyolysis-induced AKI, but the precise molecular mechanism remains unclear. In the present study, we show that macrophages released extracellular traps (ETs) comprising DNA fibers and granule proteins in a mouse model of rhabdomyolysis. Heme-activated platelets released from necrotic muscle cells during rhabdomyolysis enhanced the production of macrophage extracellular traps (METs) through increasing intracellular reactive oxygen species generation and histone citrullination. Here we report, for the first time to our knowledge, this unanticipated role for METs and platelets as a sensor of myoglobin-derived heme in rhabdomyolysis-induced AKI. This previously unknown mechanism might be targeted for treatment of the disease. Finally, we found a new therapeutic tool for prevention of AKI after rhabdomyolysis, which might rescue some sufferers of this pathology.

  • Mac-1 Signaling via Src-Family and Syk Kinases Results in Elastase-Dependent Thrombohemorrhagic Vasculopathy

    Hirahashi Junichi, Mekala Divya, Van Ziffle Jessica, Xiao Ling, Saffaripour Simin, Wagner Denisa D., Shapiro Steven D., Lowell Clifford, Mayadas Tanya N.

    Immunity (Immunity)  25 ( 2 ) 271 - 283 2006.08

    Lead author,  ISSN  1074-7613

     View Summary

    <p>CD18 integrins promote neutrophil recruitment, and their engagement activates tyrosine kinases, leading to neutrophil activation. However, the significance of integrin-dependent leukocyte activation in vivo has been difficult to prove. Here, in a model of thrombohemorrhagic vasculitis, the CD18 integrin Mac-1 on neutrophils recognized complement C3 deposited within vessel walls and triggered a signaling pathway involving the Src-family kinase Hck and the Syk tyrosine kinase. This led to neutrophil elastase release, causing hemorrhage, fibrin deposition, and thrombosis. Mice genetically deficient in any of these components (C3, Mac-1, Hck, Syk, or elastase) were resistant to disease despite normal tissue neutrophil accumulation. Disease was restored in Mac-1-deficient mice infused with wild-type, but not kinase- or elastase-deficient, neutrophils. Elastase release in the inflamed tissue was reduced in Mac-1-deficient mice, and a deficiency of Mac-1 or the kinases blocked neutrophil elastase release in vitro. These data suggest that Mac-1 engagement of complement activates tyrosine kinases to promote elastase-dependent blood vessel injury in vivo. © 2006 Elsevier Inc. All rights reserved.</p>

  • Mac-1 (CD11b/CD18) links inflammation and thrombosis after glomerular injury

    Hirahashi Junichi, Hishikawa Keiichi, Kaname Shinya, Tsuboi Naotake, Wang Yunmei, Simon Daniel I., Stavrakis George, Shimosawa Tatsuo, Xiao Ling, Nagahama Yutaka, Suzuki Kazuo, Fujita Toshiro, Mayadas Tanya N.

    Circulation (Circulation)  120 ( 13 ) 1255 - 1265 2009.09

    Lead author,  ISSN  0009-7322

     View Summary

    <p>BACKGROUND-: Inflammation and thrombosis coexist in several disorders. Although it is recognized that leukocytes may induce a procoagulant state at sites of inflammation, the critical molecular determinants of this process remain largely unknown. METHODS AND RESULTS-: To examine mechanisms of inflammation-induced thrombosis, we developed a murine model of thrombotic glomerulonephritis (TGN), a known cause of acute renal failure in patients. This model, induced by lipopolysaccharide and antibody to the glomerular basement membrane, led to rapid glomerular neutrophil recruitment, thrombotic glomerular lesions with endothelial cell injury, and renal dysfunction. In mice immunodepleted of neutrophils or lacking the leukocyte-specific integrin Mac-1, neutrophil recruitment, endothelial injury, glomerular thrombosis, and acute renal failure were markedly attenuated despite the robust generation of renal cytokines. Neutrophil elastase is a likely effector of Mac-1 because its activity was reduced in Mac-1-deficient mice and the phenotype in mice deficient in Mac-1 or neutrophil elastase was similar. Platelets accumulated in glomerular capillaries within 4 hours of TGN before evidence of thrombosis. Platelet immunodepletion before TGN markedly exacerbated hematuria (hemorrhage), inflammation, and injury, whereas thrombocytopenic Mac-1-deficient mice remained resistant to disease, indicating that initial glomerular platelet deposition protects the vessel wall from neutrophil-mediated sequelae. The subsequent thrombosis relied on the interaction of Mac-1 on recruited neutrophils with glycoprotein Ibα on platelets as antibody-mediated disruption of this interaction attenuated TGN without affecting renal neutrophil accumulation. CONCLUSIONS-: These observations establish Mac-1 on neutrophils as a critical molecular link between inflammation and thrombosis and suggest it as an attractive target for antithrombotic therapy.</p>

  • Lactoferrin Suppresses Neutrophil Extracellular Traps Release in Inflammation

    Okubo Koshu, Kamiya Mako, Urano Yasuteru, Nishi Hiroshi, Herter Jan M., Mayadas Tanya, Hirohama Daigoro, Suzuki Kazuo, Kawakami Hiroshi, Tanaka Mototsugu, Kurosawa Miho, Kagaya Shinji, Hishikawa Keiichi, Nangaku Masaomi, Fujita Toshiro, Hayashi Matsuhiko, Hirahashi Junichi

    EBioMedicine (EBioMedicine)  10   204 - 215 2016.08

    Last author, Corresponding author

     View Summary

    <p>Neutrophils are central players in the innate immune system. They generate neutrophil extracellular traps (NETs), which protect against invading pathogens but are also associated with the development of autoimmune and/or inflammatory diseases and thrombosis. Here, we report that lactoferrin, one of the components of NETs, translocated from the cytoplasm to the plasma membrane and markedly suppressed NETs release. Furthermore, exogenous lactoferrin shrunk the chromatin fibers found in released NETs, without affecting the generation of oxygen radicals, but this failed after chemical removal of the positive charge of lactoferrin, suggesting that charge-charge interactions between lactoferrin and NETs were required for this function. In a model of immune complex-induced NET formation in vivo, intravenous lactoferrin injection markedly reduced the extent of NET formation. These observations suggest that lactoferrin serves as an intrinsic inhibitor of NETs release into the circulation. Thus, lactoferrin may represent a therapeutic lead for controlling NETs release in autoimmune and/or inflammatory diseases. </p>

  • IL-15, a survival factor for kidney epithelial cells, counteracts apoptosis and inflammation during nephritis

    Shinozaki Michiya, Hirahashi Junichi, Lebedeva Tatiana, Liew Foo Y., Salant David J., Maron Ruth, Kelley Vicki Rubin

    Journal of Clinical Investigation (Journal of Clinical Investigation)  109 ( 7 ) 951 - 960 2002

    ISSN  0021-9738

     View Summary

    <p>IL-15, a T cell growth factor, has been linked to exacerbating autoimmune diseases and allograft rejection. To test the hypothesis that IL-15-deficient (IL-15-/-) mice would be protected from T cell-dependent nephritis, we induced nephrotoxic serum nephritis (NSN) in IL-15-/- and wild-type (IL-15+/+) C57BL/6 mice. Contrary to our expectations, IL-15 protects the kidney during this T cell-dependent immunologic insult. Tubular, interstitial, and glomerular pathology and renal function are worse in IL-15-/- mice during NSN. We detected a substantial increase in tubular apoptosis in IL-15-/- kidneys. Moreover, macrophages and CD4 T cells are more abundant in the interstitia and glomeruli in IL-15-/- mice. This led us to identify several mechanisms responsible for heightened renal injury in the absence of IL-15. We now report that IL-15 and the IL-15 receptor (α,β,γ chains) are constitutively expressed in normal tubular epithelial cells (TECs). IL-15 is an autocrine survival factor for TECs. TEC apoptosis induced with anti-Fas or actinomycin D is substantially greater in IL-15-/- than in wild-type TECs. Moreover, IL-15 decreases the induction of a nephritogenic chemokine, MCP-1, that attracts leukocytes into the kidney during NSN. Taken together, we suggest that IL-15 is a therapeutic for tubulointerstitial and glomerular kidney diseases.</p>

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Papers, etc., Registered in KOARA 【 Display / hide

Reviews, Commentaries, etc. 【 Display / hide

  • 【NETs関連総説】NETsと自己免疫疾患

    平橋 淳一

    日本血栓止血学会誌 ((一社)日本血栓止血学会)  32 ( 6 ) 679 - 686 2021.12

    ISSN  0915-7441

     View Summary

    新たな生体防御機構として2004年に発見された好中球細胞外トラップ(neutrophil extracellular traps:NETs)は、自然免疫にとどまらずその制御不全が自己免疫疾患にも根本的に関わることが明らかとなってきた。NETsは自己免疫疾患の発症と進展へ少なくとも次の4つの点で寄与している。(1)病原性自己抗体産生における自己寛容(tolerance)の破綻(2)NETs成分の露出による自己抗原の供給(3)炎症の増幅(4)炎症に伴う血栓症(thromboinflammation)である。2007年、NETsが臓器損傷を誘発して宿主を傷つける可能性が初めて示唆されたのを契機に、NETosis阻害により様々な感染症における組織損傷を軽減できることが報告され、現在では、全身性エリテマトーデス(systemic lupus erythematosus:SLE)、関節リウマチ(rheumatoid arthritis:RA)、糖尿病、アテローム性動脈硬化症、全身性血管炎、血栓症、がんの転移、創傷治癒、外傷など様々な病態に関与していることが報告されている。しかし、NETsは本来生体防御機構の一つであり、感染防御のみならず何らかの有益な機能を果たしている可能性も忘れてはならず、NETsの制御法は重要な研究テーマの一つとなっている。(著者抄録)

  • 【急速進行性腎炎症候群-Up date】ANCA関連血管炎 臨床

    大久保 光修, 平橋 淳一

    腎と透析 ((株)東京医学社)  91 ( 3 ) 379 - 385 2021.09

    ISSN  0385-2156

  • 【腎疾患治療薬update】(第1章)腎疾患患者への薬の使い方 糸球体腎炎 糸球体腎炎における抗血栓療法

    大久保 光修, 平橋 淳一

    腎と透析 ((株)東京医学社)  91 ( 増刊 ) 58 - 64 2021.08

    ISSN  0385-2156

  • 亜鉛製剤投与による低銅血症でESA抵抗性貧血と汎血球減少を呈した一症例

    平橋 淳一, 坂東 美和

    日本透析医学会雑誌 ((一社)日本透析医学会)  54 ( Suppl.1 ) 518 - 518 2021.05

    Research paper, summary (national, other academic conference),  ISSN  1340-3451

  • 【腎疾患コンサルテーション】急性腎障害(AKI) 横紋筋融解症/クラッシュシンドロームへの対応

    平橋 淳一

    腎と透析 ((株)東京医学社)  89 ( 4 ) 546 - 549 2020.10

    ISSN  0385-2156

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Presentations 【 Display / hide

  • MAC-1 (CD11B/CD18)- Mediated Macrophage Extracellular Traps Production is Critical to RhabdomyolysisInduced Acute Kidney Injury

    Junichi Hirahashi

    The 15th Asian Pacific Congress of Nephrology & 52nd Australian and New Zealand Society of Nephrology Annual Scientific Meeting , 

    2016.09

    Oral presentation (general)

  • Lactoferrin modulates “Immunothrombosis” in inflammatory diseases

    Hirahashi Junichi

    第12回 ラクトフェリン国際会議 (名古屋), 

    2015.11

Research Projects of Competitive Funds, etc. 【 Display / hide

  • Development of a novel therapeutic peptide for crush syndrome targetting leukocyte extracellular traps

    2022.04
    -
    Present

    基盤研究(B), Research grant, No Setting

  • 血小板ー白血球コンタクトの免疫学的解析による炎症メカニズムの解明と新規治療の開発

    2018.04
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

  • Investigation of Dysregulated Immunothrombosis in inflammatory diseases and development of a new therapeutic tool.

    2015.04
    -
    2018.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

  • フェントン反応による好中球細胞外捕捉現象制御機構の解明と難治性血管炎治療への応用

    2012.04
    -
    2015.03

    Research grant, Principal investigator

Intellectual Property Rights, etc. 【 Display / hide

  • 白血球の細胞外トラップ形成阻害活性を有するペプチド

    Date applied: 特願2021-185133  2021.11 

    Patent

  • 白血球の細胞外トラップ形成の阻害剤

    Date applied: 2014-207415  2014.10 

    Patent, Joint

  • 白血球の細胞外トラップ形成の阻害剤

    Date applied: 2013-081243  2013.04 

    Patent, Joint

  • ANCA関連血管炎治療薬

    Date applied: 2010-525718  2009.08 

    Patent, Joint

Awards 【 Display / hide

  • 2006年度 東京大学医学部 Best Teacher’s Award

    2006

  • 2004 ASIP TRAINEE TRAVEL AWARD in Experimental Biology

    2004

 

Courses Taught 【 Display / hide

  • GENERAL MEDICINE

    2022

  • GENERAL MEDICINE

    2021

  • GENERAL MEDICINE

    2020

  • GENERAL MEDICINE

    2019

Courses Previously Taught 【 Display / hide

  • 総合診療における健康問題、生活習慣病へのアプローチ

    慶應義塾大学医学部

    2021.04
    -
    2022.03

    Lecture, Within own faculty

  • 総合診療における健康問題、生活習慣病へのアプローチ

    慶應義塾大学医学部

    2021.04
    -
    2022.03

    Lecture, Within own faculty

  • 総合診療における健康問題、生活習慣病へのアプローチ

    慶應義塾大学医学部 総合診療科

    2019.04
    -
    2020.03

    Full academic year, Lecture, Within own faculty

  • 炎症性疾患の分野横断的アプローチ:不明熱の鑑別

    慶應義塾大学医学部 総合診療科

    2018.04
    -
    2019.03

    Spring Semester, Lecture, Within own faculty

  • 炎症性疾患の分野横断的アプローチ

    慶應義塾大学医学部 総合診療科

    2017.04
    -
    2018.03

    Spring Semester, Lecture

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Educational Activities and Special Notes 【 Display / hide

  • H27 日本腎臓学会東部会 教育講演 「よくわかるシリーズ」ANCA関連血管炎の免疫学と治療

    2015
    -
    Present

    , Lecture at Education Method and Practice

  • H22 日本腎臓学会総会 教育講演 「よくわかるシリーズ」ANCA関連血管炎/腎炎の基礎メカニズム

    2010
    -
    Present

    , Lecture at Education Method and Practice

 

Media Coverage 【 Display / hide

  • タモリ x 山中伸弥 人体 vs ウイルス 驚異の免疫ネットワーク

    NHKスペシャル,  (動画) , 2021.07

     View Summary

    好中球細胞外トラップのリアルタイム細胞イメージング画像の提供

  • 急性腎障害 仕組み解明 慶大、新たな治療法に道

    日経産業新聞 (朝刊 6面) , 2018.01

  • クラッシュ症候群仕組み解明

    朝日新聞 朝刊 (3面) , 2018.01

  • 日本の研究班の成果に大きな反響 ー国際ラクトフェリン学会ー

    健康産業新聞, 2013.11

  • 地震で下敷き…腎不全に クラッシュ症候群の仕組み解明

    朝日新聞デジタル, 2018.01

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Committee Experiences 【 Display / hide

  • 2018
    -
    2019

    難治性腎障害に関する調査研究班 RPGN診療ガイドライン作成委員, 厚生労働省難治性腎障害に関する調査研究班

  • 2017.01
    -
    2018.03

    日本腎臓学会 ISN Frontiers 2018 アワード・YIA小委員会, 日本腎臓学会

  • 2017
    -
    2018

    CKD診療ガイド・ガイドライン2018作成委員会, 日本腎臓学会

  • 2013
    -
    2014

    ANCA関連血管炎の診療ガイドライン 2014年改訂版 作成委員, 厚生労働省 難治性疾患克服研究事業

  • 2013
    -
    2014

    急速進行性腎炎症候群(RPGN)診療ガイドライン 2014年 作成委員, 厚生労働科学研究費補助金 難治性疾患等克服研究事業 (難治性疾患克服研究事業)「進行性腎障害に関する調査研究」 診療ガイドライン作成分科会 

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