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Association between oxidative stress and Type2 inflammation in asthma

Research Project

Project/Area Number 21K16117
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53030:Respiratory medicine-related
Research InstitutionKindai University (2023)
Kyoto University (2021-2022)

Principal Investigator

nagasaki tadao  近畿大学, 奈良病院, 講師 (40747862)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2023: ¥130,000 (Direct Cost: ¥100,000、Indirect Cost: ¥30,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2021: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Keywordsasthma / redox balance / glutathione / ferroptosis / SLC7A11 / 15 lipoxygenase-1 / Type-2 inflammation / 喘息 / ヒト気道上皮細胞 / 酸化ストレス / 2型炎症
Outline of Research at the Start

喘息病態の悪化に酸化ストレスが関連していることが知られているが、その正確な機序は不明である。今回、酸化ストレスと喘息の主な病態である気道炎症との関連を明らかにするため、以下の項目に着目する。
①Th2サイトカインや好酸球性炎症は酸化ストレスを増悪させるか、②Th17サイトカインや好中球性炎症は酸化ストレスを増悪させるか、③2型炎症や非2型炎症を軽減することで酸化ストレスが軽減するか、④酸化ストレスは2型炎症や非2型炎症を増強させるか、⑤酸化ストレスを軽減することで2型炎症や非2型炎症は軽減するか

Outline of Final Research Achievements

GSSG was higher and GSH:GSSG lower in asthmatic compared to HC BAL fluid. In contrast, fresh asthmatic HAEC intracellular GSH levels were lower but correlated with BAL fluid GSH. In vitro, the T2 cytokine IL-13 induced. 15LO1 activity increased hydroperoxy-phospholipids, in association with lowered intracellular GSH and higher extracellular GSSG levels. Lowering GSH levels further by inhibiting SLC7A11 (erastin) enhanced T2 inflammatory protein expression and cell death. Ex vivo, GSH and GSSG-associated imbalances in redox biology corresponded with altered 15LO1 and SLC7A11 expression, increased ferroptotic phospholipids, as well as Type-2 biomarkers and worsened clinical outcomes. Thus, 15LO1 pathway activity-induced perturbations in GSH:GSSG promote T2 inflammation and poor asthma control. 15LO1 is a novel therapeutic target for asthma.

Academic Significance and Societal Importance of the Research Achievements

生物学的製剤を含めた喘息治療の進展にもかかわらず、難治性喘息がいまだ存在する。今までとは異なったアプローチから喘息治療を検討する必要がある。
喘息含めた疾患の病態生理において、酸化ストレスが関わっていることが示されており、近年、新しい細胞死であるフェロトーシスが喘息に関わっていることが明らかになった。
今回、フェロトーシスに関連あるグルタチオンを喘息患者および喘息患者の起動細胞を用いて検討した。2型炎症、15LO1、グルタチオン、フェロトーシスの関連を明らかにし、特に15LO1が新たな治療ターゲットとなる可能性を示した。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (10 results)

All 2024 2023 2022

All Journal Article (7 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 7 results,  Open Access: 4 results) Presentation (3 results) (of which Invited: 1 results)

  • [Journal Article] Evaluation of elevated plasma fatty acids as relevant factors for adult-onset asthma: The Nagahama Study2024

    • Author(s)
      Tashima Noriyuki、Matsumoto Hisako、Nishi Kenta、Terada Satoru、Kogo Mariko、Nomura Natsuko、Morimoto Chie、Sunadome Hironobu、Nagasaki Tadao、Oguma Tsuyoshi、Nakatsuka Yoshinari、Murase Kimihiko、Kawaguchi Takahisa、Tabara Yasuharu、Chin Kazuo、Sonomura Kazuhiro、Matsuda Fumihiko、Hirai Toyohiro
    • Journal Title

      Allergology International

      Volume: 73 Issue: 1 Pages: 65-70

    • DOI

      10.1016/j.alit.2023.04.005

    • ISSN
      1323-8930, 1440-1592
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sputum microbiota and inflammatory subtypes in asthma, COPD, and its overlap2024

    • Author(s)
      Morimoto Chie、Matsumoto Hisako、Nomura Natsuko、Sunadome Hironobu、Nagasaki Tadao、Sato Susumu、Sato Atsuyasu、Oguma Tsuyoshi、Ito Isao、Kogo Mariko、Tomii Keisuke、Tajiri Tomoko、Ohashi Kai、Tsukahara Takamitsu、Hirai Toyohiro
    • Journal Title

      Journal of Allergy and Clinical Immunology: Global

      Volume: 3 Issue: 1 Pages: 100194-100194

    • DOI

      10.1016/j.jacig.2023.100194

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Increased blood eosinophils and airflow obstruction as new-onset asthma predictors in the elderly: The Nagahama study2024

    • Author(s)
      Nishi Kenta、Nagasaki Tadao、Matsumoto Hisako、Oguma Tsuyoshi、Terada Satoru、Nomura Natsuko、Kogo Mariko、Tashima Noriyuki、Sunadome Hironobu、Murase Kimihiko、Matsumoto Takeshi、Kawaguchi Takahisa、Tabara Yasuharu、Matsuda Fumihiko、Sato Susumu、Chin Kazuo、Hirai Toyohiro
    • Journal Title

      Allergology International

      Volume: 73 Issue: 2 Pages: 236-242

    • DOI

      10.1016/j.alit.2023.11.002

    • ISSN
      1323-8930, 1440-1592
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Associations between Nocturnal Hypoxemia and Retinal Nerve Fiber Layer Thinning: The Nagahama Study2024

    • Author(s)
      Nagasaki Tadao、Miyake Masahiro、Sato Susumu、Murase Kimihiko et al.
    • Journal Title

      Annals of the American Thoracic Society

      Volume: 21 Issue: 4 Pages: 644-650

    • DOI

      10.1513/annalsats.202304-355oc

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effectiveness of bronchial thermoplasty in patients with asthma exhibiting overweight/obesity and low quality of life2023

    • Author(s)
      Nishi Kenta、Yoshimura Chie、Morita Kyohei、Ishikawa Ryoichi、Toyokura Erika、Nagasaki Tadao、Matsumoto Hisako、Nishizaka Yasuo
    • Journal Title

      World Allergy Organization Journal

      Volume: 16 Issue: 3 Pages: 100756-100756

    • DOI

      10.1016/j.waojou.2023.100756

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 15LO1 dictates glutathione redox changes in asthmatic airway epithelium to worsen type 2 inflammation2022

    • Author(s)
      Nagasaki T, Schuyler AJ, Zhao J, Samovich SN, Yamada K, Deng Y, Ginebaugh SP, Christenson SA, Woodruff PG, Fahy JV, Trudeau JB, Stoyanovsky D, Ray A, Tyurina YY, Kagan VE, Wenzel SE.
    • Journal Title

      J Clin Invest.

      Volume: 132 Issue: 1

    • DOI

      10.1172/jci151685

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Age-specific associations of early daycare, older siblings, severe airway infection, and preterm birth with subsequent atopic diseases2022

    • Author(s)
      Nagasaki T, Tabuchi T, Matsumoto H, Horimukai K.
    • Journal Title

      Pediatr Allergy Immunol.

      Volume: 33 Issue: 4

    • DOI

      10.1111/pai.13771

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] 2型炎症におけるフェロトーシス2024

    • Author(s)
      長崎忠雄
    • Organizer
      日本呼吸器学会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 酸化ストレスと2型炎症2023

    • Author(s)
      長崎忠雄
    • Organizer
      日本呼吸器学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 成人喘息の新規発症に関わるリスク因子における性差2022

    • Author(s)
      長崎忠雄、西健太、松本久子、小熊毅、砂留広伸、村瀬公彦、松本健、田嶋範之、野村奈都子、古郷摩利子、寺田悟、田原康玄、松田文彦、佐藤晋、陳和夫、平井豊博
    • Organizer
      日本呼吸器学会
    • Related Report
      2022 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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