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Elucidation of the role of the nitric oxide synthase system in the pathogenesis of respiratory diseases

Research Project

Project/Area Number 19K08657
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53030:Respiratory medicine-related
Research InstitutionUniversity of the Ryukyus

Principal Investigator

Tsutsui Masato  琉球大学, 医学(系)研究科(研究院), 教授 (70309962)

Co-Investigator(Kenkyū-buntansha) 松崎 俊博  琉球大学, 医学(系)研究科(研究院), 助教 (50244330)
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: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords一酸化窒素 / 一酸化窒素合成酵素 / 肺気腫 / マウス / 呼吸器疾患 / Wnt/β-catenin経路 / 遺伝子欠損マウス / 多様性
Outline of Research at the Start

呼吸器疾患における一酸化窒素(NO)合成酵素(NOSs)系の役割は十分に明らかにされていない。私達は、肺線維症や肺高血圧ではNOSs系は有益な役割を果たしているが、気管支喘息ではNOSs系は真逆の有害な役割を演じていることを見出した。この結果から、同じ肺の病気であってもNOSs系の役割は病態が異なれば異なることが示唆された。この自身の研究成果を踏まえて、申請者は、呼吸器疾患におけるNOSs系の役割の多様性を包括的に解明することを着想した。この目的のために、本研究では、肺気腫、急性肺障害、および敗血症性ショックにおけるNOSs系の役割をトリプルn/i/eNOSs-/-マウスを用いて検討する。

Outline of Final Research Achievements

Three isoforms of nitric oxide (NO) synthases (nNOS、iNOS、eNOS) are expressed in human pulmonary emphysematous lesions. However, the role of the NOSs system in the pathogenesis of pulmonary emphysema remains to be elucidated. We investigated this issue in mice lacking all three NOS isoforms (triple n/i/eNOSs-/- mice). We demonstrated that the triple NOSs-/- mice exhibited spontaneous development of pulmonary emphysema, and that mRNA expression levels of Wnt/β-catenin pathway-related genes were reduced in the lung of the triple NOSs-/- mice. These results suggest that the NOSs system plays an important role in the prevention of pulmonary emphysema, and that down-regulation of the Wnt/β-catenin pathway is involved in the pathogenesis of spontaneous pulmonary emphysema in the triple NOSs-/- mice.

Academic Significance and Societal Importance of the Research Achievements

以前に肺気腫や慢性気管支炎と呼ばれていた病態は、現在では慢性閉塞性肺疾患(COPD)と総称されている。COPDは日本人の死因の第9位を占めている。高齢化のためにCOPD患者は増加し続けており、10年後には日本人の死因の第3位になると予想されている。しかし、COPDの成因に不明な点が多いため、COPDの根治的治療法はいまだ開発されていない。私達は、本研究において、肺気腫の成因にNOSs系が役割を果たしていること、および、その分子機序にはWnt/β-catenin経路の発現低下が関与していることを明らかにした。本研究の知見は、肺気腫の全く新しい治療法の開発に繋がる成果である。

Report

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

    (14 results)

All 2021 2020 2019 Other

All Journal Article (4 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (8 results) (of which Int'l Joint Research: 3 results,  Invited: 1 results) Remarks (2 results)

  • [Journal Article] Spontaneous pulmonary emphysema in mice lacking all three nitric oxide synthase isoforms2021

    • Author(s)
      Kato Kaori、Tsutsui Masato、Noguchi Shingo、Iha Yukitoshi、Naito Keisuke、Ogoshi Takaaki、Nishida Chinatsu、Tahara Masahiro、Yamashita Hirotaka、Wang Ke-Yong、Toyohira Yumiko、Yanagihara Nobuyuki、Masuzaki Hiroaki、Shimokawa Hiroaki、Tanimoto Akihide、Yatera Kazuhiro
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 22088-22088

    • DOI

      10.1038/s41598-021-01453-6

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] NOX1/NADPH oxidase in bone marrow-derived cells modulates intestinal barrier function2020

    • Author(s)
      Liu J, Iwata K, Zhu K, Matsumoto M, Asaoka N, Zhang X, Ibi M, Katsuyama M, Tsutsui M, Kato S, and Yabe-Nishimura C
    • Journal Title

      Free Radical Biology and Medicine

      Volume: 147 Pages: 90-101

    • DOI

      10.1016/j.freeradbiomed.2019.12.009

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Inhibitory effects of Sho-ju-sen and its component kumazasa leaves on catecholamine secretion induced by acetylcholine in cultured bovine adrenal medullary cells2020

    • Author(s)
      Li X, Yanagihara N, Horishita T, Toyohira Y, Satoh N, Tsutsui T, Kita T
    • Journal Title

      Current Topics in Phytochemistry

      Volume: 16 Pages: 105-114

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Protective role of myelocytic nitric oxide synthases in pulmonary hypertension due to lung diseases and/or hypoxia2020

    • Author(s)
      生越貴明, 筒井正人, 矢寺和博, 迎寛
    • Journal Title

      Folia Pharmacologica Japonica

      Volume: 155 Issue: 2 Pages: 69-73

    • DOI

      10.1254/fpj.19111

    • NAID

      130007804224

    • ISSN
      0015-5691, 1347-8397
    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] Spontaneous pulmonary emphysema in mice lacking all three nitric oxide synthase isoforms2021

    • Author(s)
      Kato K, Tsutsui M, Noguchi S, Naito K, Ogoshi T, Tahara M, Yatera K
    • Organizer
      The 25th Annual Congress of the Asian Pacific Society of Respirology (APSR 2021)
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Diversity of roles of nitric oxide synthases in the pathogenesis of lung diseases2021

    • Author(s)
      Tsutsui M, Kato K, Ogoshi T, Noguchi S, Yatera K
    • Organizer
      The 94th Annual Meeting of the Japanese Pharmacological Society
    • Related Report
      2020 Research-status Report
  • [Presentation] Spontaneous development of pulmonary emphysema in mice lacking all three nitric oxide synthases2020

    • Author(s)
      Kato K, Tsutsui M, Noguchi S, Naito K, Ogoshi T, Wang KY, Shimokawa H, Yatera K
    • Organizer
      The American Thoracic Society 2020 International Conference
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] 呼吸器疾患の成因におけるNO合成酵素系の役割の多様性2020

    • Author(s)
      筒井正人、加藤香織、生越貴明、矢寺和博
    • Organizer
      第30回日本循環薬理学会
    • Related Report
      2020 Research-status Report
  • [Presentation] 一酸化窒素合成酵素完全欠損マウスは肺気腫を自然発症する2020

    • Author(s)
      加藤香織、筒井正人、野口真吾、内藤圭佑、生越貴明、矢寺和博
    • Organizer
      第60回日本呼吸器学会学術講演会
    • Related Report
      2020 Research-status Report
  • [Presentation] Protective role of nitric oxide synthases in pulmonary emphysema in mice2019

    • Author(s)
      Kato K, Tsutsui M, Noguchi S, Naito K, Ogoshi T, Wang KY, Shimokawa H, Yatera K
    • Organizer
      29th International Congress of the European Respiratory Society
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 生体における一酸化窒素合成酵素系の意義2019

    • Author(s)
      筒井正人
    • Organizer
      第49回日本心脈管作動物質学会年会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 肺気腫病変形成における一酸化窒素合成酵素系の保護的役割2019

    • Author(s)
      筒井正人
    • Organizer
      第72回日本薬理学会西南部会
    • Related Report
      2019 Research-status Report
  • [Remarks] 一酸化窒素(NO)産生障害が肺気腫を引き起こすことを発見 世界初

    • URL

      https://www.u-ryukyu.ac.jp/news/29461/

    • Related Report
      2021 Annual Research Report
  • [Remarks] 琉球大学大学院医学研究科薬理学ホームページ

    • URL

      http://w3.u-ryukyu.ac.jp/pharmaco/Pharmacology/youkoso_yao_lihe.html

    • Related Report
      2019 Research-status Report

URL: 

Published: 2019-04-18   Modified: 2023-01-30  

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