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Fundamental research for the development of a new strategy for the treatment of severe pulmonary hypertension by IL-6 blockade

Research Project

Project/Area Number 19K08506
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionNational Cardiovascular Center Research Institute

Principal Investigator

Inagaki Tadakatsu  国立研究開発法人国立循環器病研究センター, 研究所, 上級研究員 (20638366)

Co-Investigator(Kenkyū-buntansha) 石橋 知彦  国立研究開発法人国立循環器病研究センター, 研究所, 上級研究員 (30722285)
中岡 良和  国立研究開発法人国立循環器病研究センター, 研究所, 部長 (90393214)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords肺高血圧症 / interleukin-6 / 炎症性サイトカイン / 肺血管リモデリング / 肺動脈性肺高血圧症 / 血管リモデリング / Interleukin-6 / ヘルパーT細胞 / 炎症 / 右心不全
Outline of Research at the Start

本研究は、厚生労働省指定難病のひとつである肺動脈性肺高血圧症(PAH)の病態解明及び新規治療法の開発を目標としている。PAH患者の肺で観察される肺血管の異常なリモデリングの進行過程において炎症性サイトカインのinterleukin-6(IL-6)シグナルに着目し、IL-6が関与する細胞を明らかにし、IL-6阻害によるPAHの新規治療法の確立のため、心臓に対するIL-6阻害の影響を明らかにすること、またIL-6阻害が有効なPAHのサブタイプを患者血清サンプルにおける網羅的な血清サイトカインのプロファイル解析を行うことにより明らかにすることを目的としている。

Outline of Final Research Achievements

Pulmonary arterial hypertension (PAH) is an refractory disease designated by the Ministry of Health, Labour and Welfare (MHLW) with a poor prognosis, and the immediate elucidation of its cause and the development of a curative treatment are desired. In this study, we aimed to elucidate the role of interleukin-6 (IL-6) in the pathogenesis of PAH by using a rat system capable of generating a severe PAH model, and to elucidate the mechanism of PAH pathogenesis. IL-6 is involved in the pathogenesis of pulmonary hypertension not only in mild to moderate hypoxic pulmonary hypertension models, but also in severe PH models, MCT and SuHx models.Furthermore, our results suggest that IL-6 signaling in CD4-positive cells has a central role in the pathogenesis of PAH. Our results indicate that IL-6 inhibition may be a novel and promising treatment for refractory PAH.

Academic Significance and Societal Importance of the Research Achievements

肺高血圧症は、治療薬の開発が進み治療法が進歩しつつある疾患であるが、薬剤に適応しない患者については未だに予後不良の疾患である。本研究では炎症性サイトカインのIL-6が軽度から重症の肺高血圧症の病態形成に関与することを明らかにした。また、免疫細胞のヘルパーT細胞におけるIL-6シグナルがPH病態形成に関与することが示唆されたことから、炎症に着目した新たな治療法の確立といった肺高血圧症における創薬の可能性や、これまでの既存の薬剤に適応しない重症肺高血圧患者の予後改善にまで発展する可能性が期待できる。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (11 results)

All 2021 2020 2019

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (7 results) (of which Int'l Joint Research: 2 results) Book (1 results)

  • [Journal Article] Evaluation of right coronary vascular dysfunction in severe pulmonary hypertensive rats using synchrotron radiation microangiography2021

    • Author(s)
      Inagaki Tadakatsu、Pearson James T.、Tsuchimochi Hirotsugu、Schwenke Daryl O.、Saito Shigeyoshi、Higuchi Takahiro、Masaki Takeshi、Umetani Keiji、Shirai Mikiyasu、Nakaoka Yoshikazu
    • Journal Title

      American Journal of Physiology-Heart and Circulatory Physiology

      Volume: 320 Issue: 3 Pages: H1021-H1036

    • DOI

      10.1152/ajpheart.00327.2020

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension2021

    • Author(s)
      Masaki T, Okazawa M, Asano R, Inagaki T, Ishibashi T, Yamagishi A, Umeki-Mizushima S, Nishimura M, Manabe Y, Ishibashi-Ueda H, Shirai M, Tsuchimochi H, Pearson JT, Kumanogoh A, Sakata Y, Ogo T, Kishimoto T, Nakaoka Y
    • Journal Title

      Proc Natl Acad Sci U S A

      Volume: 118 Issue: 11

    • DOI

      10.1073/pnas.2023899118

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pristane/Hypoxia (PriHx) Mouse as a Novel Model of Pulmonary Hypertension Reflecting Inflammation and Fibrosis2020

    • Author(s)
      Mori Hiroyoshi、Ishibashi Tomohiko、Inagaki Tadakatsu、Okazawa Makoto、Masaki Takeshi、Asano Ryotaro、Manabe Yusuke、Ohta-Ogo Keiko、Narazaki Masashi、Ishibashi-Ueda Hatsue、Kumanogoh Atsushi、Nakaoka Yoshikazu
    • Journal Title

      Circulation Journal

      Volume: 84 Issue: 7 Pages: 1163-1172

    • DOI

      10.1253/circj.CJ-19-1102

    • NAID

      130007864283

    • ISSN
      1346-9843, 1347-4820
    • Year and Date
      2020-06-25
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Anti-interleukin-21 aptamer treatment improves pathology in a rodent models of pulmonary hypertension.2021

    • Author(s)
      Tadakatsu Inagaki, Ryotaro Asano, Marie Mitsui, Tomohiko Ishibashi, Makoto Okazawa, Takeshi Ogo, Yoshikazu Nakaoka
    • Organizer
      The 5th JCS Council Forum on Basic Cardio Vascular Research
    • Related Report
      2021 Annual Research Report
  • [Presentation] 肺高血圧症におけるIL-6の重要性:遺伝子改変ラットを用いた検討2021

    • Author(s)
      稲垣薫克、石橋知彦、岡澤慎、正木豪、真鍋侑資、浅野遼太郎、大郷剛、中岡良和
    • Organizer
      第29回日本血管生物医学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Critical Roles of Interleukin-21 Signaling in the Pathogenesis of Pulmonary Arterial Hypertension2020

    • Author(s)
      Tadakatsu Inagaki, Tomohiko Ishibashi, Makoto Okazawa, Takeshi Masaki, Marie Mitsui, Kazuteru Aoki, Ryotaro Asano, Takeshi Ogo, Yoshikazu Nakaoka
    • Organizer
      The 21st International Vascular Biology Meeting
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] gp130 Signaling in CD4 Cells Is Important for the Pathogenesis of Pulmonary Arterial Hypertension2020

    • Author(s)
      Tomohiko Ishibashi, Takeshi Masaki, Tadakatsu Inagaki, Makoto Okazawa, Yoshikazu Nakaoka
    • Organizer
      The 21st International Vascular Biology Meeting
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Interleukin-21阻害による肺動脈性肺高血圧症の新規治療法開発2020

    • Author(s)
      稲垣 薫克,浅野 遼太郎,石橋 知彦,岡澤 慎,正木 豪,三井 麻利江,青木 一晃,大郷 剛,中岡 良和
    • Organizer
      第5回日本肺高血圧・肺循環学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 炎症性サイトカインシグナル阻害によるPAHの新規治療法開発2019

    • Author(s)
      稲垣薫克、大郷剛、中岡良和
    • Organizer
      第4回日本肺高血圧・肺循環学会
    • Related Report
      2019 Research-status Report
  • [Presentation] CD4陽性細胞におけるgp130シグナルは肺高血圧症の病態形成に重要である2019

    • Author(s)
      石橋知彦、正木豪、稲垣薫克、森啓悦、浅野遼太郎、岡澤慎、中岡良和
    • Organizer
      第27回日本血管生物医学会
    • Related Report
      2019 Research-status Report
  • [Book] Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertension2020

    • Author(s)
      Nakanishi, T., Baldwin, S.H., Fineman, J.R., Yamagishi, H
    • Total Pages
      405
    • Publisher
      Springer Nature
    • ISBN
      9789811511844
    • Related Report
      2020 Research-status Report

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Published: 2019-04-18   Modified: 2024-12-25  

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