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Investigation of involvement of hypoxia-inducible factor 1 on cigarette smoke-induced airway and lung pathological events

Research Project

Project/Area Number 16K10974
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Anesthesiology
Research InstitutionKansai Medical University

Principal Investigator

NISHI Kenichiro  関西医科大学, 医学部, 研究員 (50340716)

Co-Investigator(Kenkyū-buntansha) 広田 喜一  関西医科大学, 医学部, 教授 (00283606)
Research Collaborator MATSUO Yoshiyuki  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywordsタバコ / HIF-1 / 低酸素誘導性因子1 / 酸素代謝 / 慢性閉塞性肺疾患 / 活性酸素 / 周術期 / 炎症 / 気道
Outline of Final Research Achievements

Cigarette smoke (CS) is a major contributor to the development of a large number of fatal and debilitating disorders. However, the precise molecular mechanisms underlying the effects of CS in lung disease are largely unknown. To elucidate these pathophysiological processes, we examined the n vitro and in vivo effects of CS extract (CSE) and CS on the transcription factor, hypoxia-inducible factor 1 (HIF-1). CSE induced concentration- and time-dependent accumulation of HIF-1α protein in human lung epithelial-like cells under non-hypoxic conditions. Further investigation revealed that reactive oxygen species were generated in cells exposed to CSE and were required for CSE-mediated induction of HIF-1α protein, as was activation of phosphoinositide 3-kinase and mitogen-activated protein kinase pathways. In conclusion, we demonstrated that CSE and CS induced HIF-1 activation in vitro and in vivo, respectively.

Academic Significance and Societal Importance of the Research Achievements

生体の低酸素応答研究の流れに沿った本申請の研究は、細胞内に内在する酸素分圧感知機構とその下流の転写因子、HIF-1の機能と喫煙が生体にもたらす影響を関連づけて解析するという従来にはなかった観点を持ち新規性を有している。このような周術期合併症との関連に加えて慢性的なタバコへの暴露が肺胞上皮機能の機能のみならず肺の解剖学的な再構築を経た肺線維症にいたる過程も視野に収めた研究成果が得られた。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report

Research Products

(21 results)

All 2019 2018 2017 2016

All Journal Article (14 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 11 results,  Open Access: 9 results,  Acknowledgement Compliant: 3 results) Presentation (7 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results)

  • [Journal Article] An intimate crosstalk between iron homeostasis and oxygen metabolism regulated by the hypoxia-inducible factors (HIFs)2019

    • Author(s)
      Hirota Kiichi
    • Journal Title

      Free Radical Biology and Medicine

      Volume: 133 Pages: 118-129

    • DOI

      10.1016/j.freeradbiomed.2018.07.018

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Suppression of mitochondrial oxygen metabolism mediated by the transcription factor HIF-1 alleviates propofol-induced cell toxicity2018

    • Author(s)
      Sumi Chisato、Okamoto Akihisa、Tanaka Hiromasa、Kusunoki Munenori、Shoji Tomohiro、Uba Takeo、Adachi Takehiko、Iwai Teppei、Nishi Kenichiro、Harada Hiroshi、Bono Hidemasa、Matsuo Yoshiyuki、Hirota Kiichi
    • Journal Title

      Sci Rep

      Volume: 8 Pages: 8987-8987

    • DOI

      10.1038/s41598-018-27220-8

    • NAID

      120006539570

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 酸素生物学を読み解く 低酸素誘導性因子研究の今昔物語2018

    • Author(s)
      広田 喜一
    • Journal Title

      Life Support and Anesthesia

      Volume: 25 Pages: 897-905

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 低酸素の生物学―低酸素誘導性因子(HIF)の果たす役割2018

    • Author(s)
      広田 喜一
    • Journal Title

      Intensivist

      Volume: 10 Pages: 259-269

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Activation of hypoxia-inducible factor 1 attenuates periapical inflammation and bone loss2018

    • Author(s)
      Hirai K, Furusho H, Hirota K, Sasaki H
    • Journal Title

      Int J Oral Sci

      Volume: 10 Pages: 12-12

    • DOI

      10.1038/s41368-018-0015-0

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner2018

    • Author(s)
      Sumi Chisato、Okamoto Akihisa、Tanaka Hiromasa、Nishi Kenichiro、Kusunoki Munenori、Shoji Tomohiro、Uba Takeo、Matsuo Yoshiyuki、Adachi Takehiko、Hayashi Jun-Ichi、Takenaga Keizo、Hirota Kiichi
    • Journal Title

      PLoS One

      Volume: 13

    • DOI

      10.1371/journal.pone.0192796

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Transmembrane thioredoxin-related protein TMX1 is reversibly oxidized in response to protein accumulation in the endoplasmic reticulum2017

    • Author(s)
      Matsuo Y, Hirota K
    • Journal Title

      FEBS Open Bio

      Volume: 7 Pages: 1768-1777

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] HIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death2017

    • Author(s)
      Okamoto Akihisa、Sumi Chisato、Tanaka Hiromasa、Kusunoki Munenori、Iwai Teppei、Nishi Kenichiro、Matsuo Yoshiyuki、Harada Hiroshi、Takenaga Keizo、Bono Hidemasa、Hirota Kiichi
    • Journal Title

      Sci Rep

      Volume: 7 Pages: 3816-3816

    • DOI

      10.1038/s41598-017-03980-7

    • NAID

      120006364104

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] VHL-deficient renal cancer cells gain resistance to mitochondria-activating apoptosis inducers by activating AKT through the IGF1R-PI3K pathway2017

    • Author(s)
      Yamaguchi R, Harada H, Hirota K
    • Journal Title

      Tumour Biol

      Volume: 37 Pages: 13295-13306

    • DOI

      10.1007/s13277-016-5260-2

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Cigarette smoke reversibly activates hypoxia-inducible factor 1 in a reactive oxygen species-dependent manner2016

    • Author(s)
      Daijo H, Hoshino Y, Kai S, Suzuki K, Nishi K, Matsuo Y, Harada H, Hirota K
    • Journal Title

      Sci Rep

      Volume: 6 Pages: 34424-34424

    • DOI

      10.1038/srep34424

    • NAID

      120005850269

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The antioxidant N-acetyl cysteine suppresses lidocaine-induced intracellular reactive oxygen species production and cell death in neuronal SH-SY5Y cells2016

    • Author(s)
      Okamoto A, Tanaka M, Sumi C, Oku K, Kusunoki M, Nishi K, Matsuo Y, Takenaga K, Shingu K, Hirota K
    • Journal Title

      BMC anesthesiology

      Volume: 16 Pages: 104-104

    • DOI

      10.1186/s12871-016-0273-3

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] 硫化水素はミトコンドリア依存的に低酸素誘導性遺伝子応答を調節する2016

    • Author(s)
      甲斐 慎一, 広田 喜一
    • Journal Title

      ICUとCCU

      Volume: 40 Pages: 549-554

    • Related Report
      2016 Research-status Report
  • [Journal Article] 「酸素はいつも足りていない」の生物学の建設 - 2016年度アルバート・ラスカー基礎医学研究賞の発表に寄せて2016

    • Author(s)
      松尾 禎之, 広田 喜一
    • Journal Title

      Life Support and Anesthesia

      Volume: 24 Pages: 194-196

    • NAID

      40021124698

    • Related Report
      2016 Research-status Report
  • [Journal Article] Oxygen, Hypoxia & Beyond -2016年アルバート・ラスカー基礎医学賞に寄せて2016

    • Author(s)
      広田 喜一
    • Journal Title

      医学のあゆみ

      Volume: 259 Pages: 961-963

    • Related Report
      2016 Research-status Report
  • [Presentation] Propofol Induces Metabolic Reprogramming and Cell Death in a Mitochondria Electric Transport Chain-dependent Manner2017

    • Author(s)
      Kiichi Hirota Chisato Sumi Akihisa Okamoto, Munenori Kusunoki, Hiromasa Tanaka
    • Organizer
      Anesthesiology 2017 annual meeting
    • Related Report
      2017 Research-status Report
  • [Presentation] HIF-1-Mediated Suppression of Mitochondria Electron Transport Chain Function Confers Resistance to Lidocaine-induced Cell Death2017

    • Author(s)
      SHINICHI KAI, Kiichi Hirota, Chisato Sumi, Akihisa Okamoto, Kenichiro Nishi, Munenori Kusunoki, Yoshiyuki Matsuo, Takehiko Adachi,
    • Organizer
      Anesthesiology 2017 annual meeting
    • Related Report
      2017 Research-status Report
  • [Presentation] 抗酸化物質のN-アセチルシステインはリドカインが誘導する活性酸素種産生や細胞死を抑制する2017

    • Author(s)
      岡本 明久、楠 宗矩、角 千里、西 憲一郎、松尾 禎之、広田 喜一
    • Organizer
      第64回日本麻酔科学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] サイブリッド細胞を用いたプロポフォール細胞毒性の検討-プロポフォール注入症候群の病態生理学2017

    • Author(s)
      角 千里、廣田 喜一、楠 宗矩、岡本 明久、西 憲一郎、松尾 禎之
    • Organizer
      第64回日本麻酔科学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] サイブリッド細胞を用いたプロポフォール細胞毒性の検討2017

    • Author(s)
      角 千里、廣田 喜一、楠 宗矩、岡本 明久、西 憲一郎、松尾 禎之
    • Organizer
      第15回がんとハイポキシア研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] transmitochondrial cybrids細胞を用いたプロポフォール細胞毒性の検討-プロポフォール注入症候群の病態生理学2016

    • Author(s)
      広田 喜一, 角 千里, 楠 宗矩, 岡本 明久, 田中 宏昌, 西 憲一郎 , 松尾 禎之
    • Organizer
      第23回日本静脈麻酔学会
    • Place of Presentation
      コラッセ福島 福島市
    • Year and Date
      2016-11-19
    • Related Report
      2016 Research-status Report
  • [Presentation] 2016 年アルバート・ラスカー基礎医学賞を記念して2016

    • Author(s)
      広田 喜一
    • Organizer
      第14回がんとハイポキシア研究会
    • Place of Presentation
      岐阜グランドホテル 岐阜市
    • Year and Date
      2016-11-05
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research / Invited

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Published: 2016-04-21   Modified: 2020-03-30  

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