Hypoxia-Inducible Factor as a Therapeutic Target for Acute Respiratory Distress Syndrome

• Project/Area Number: 15K20054
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Anesthesiology
• Research Institution: Yokohama City University
• Principal Investigator: TOJO Kentaro 横浜市立大学, 医学部, 助教 (80737552)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ARDS / エネルギー代謝 / 低酸素誘導性因子 / 解糖系 / 急性呼吸促迫症候群 / プロリルヒドロキシラーゼ / 細胞死 / 肺胞上皮細胞 / 代謝リプログラミング / 肺傷害 / プロリルヒドロキシラーゼ阻害

Outline of Final Research Achievements

Bioenegertic failure due to mitochondrial dysfunction underlies the alveolar epithelial injury during acute respiratory distress syndrome (ARDS). In the present study, we demonstrated that inhibition of oxygen sensing prolyl hydroxylases (PHD) protects alveolar epithelial cells from bioenertic failure and cell death caused by experimental ARDS. The protective effects are mediated by HIF-1-dependent enhancement of glycolysis. These findings suggest that acitvation of HIF-1 might be a novel therapeutic approach for ARDS.

Research Products

• [Journal Article] Enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury (2018)
  • Author(s): Tojo Kentaro、Tamada Nao、Nagamine Yusuke、Yazawa Takuya、Ota Shuhei、Goto Takahisa
  • Journal Title: The FASEB Journal Volume: 32 Issue: 4 Pages: 2258-2268
  • DOI: 10.1096/fj.201700888r
  • Peer Reviewed
• [Journal Article] Inhibition of Prolyl Hydroxylase Attenuates Fas Ligand-Induced Apoptosis and Lung Injury in Mice (2016)
  • Author(s): Yusuke Nagamine, Kentaro Tojo, Takuya Yazawa, Shunsuke Takaki, Yasuko Baba, Takahisa Goto, Kiyoyasu Kurahashi
  • Journal Title: American Journal of Respiratory Cell and Molecular Biology Volume: 55 Issue: 6 Pages: 878-888
  • DOI: 10.1165/rcmb.2015-0266oc
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Metabolic reprogramming by inhibition of prolyl hydroxylases protects alveolar epithelial cells from LPS-neutrophil-induced energy derangements and cell death (2017)
  • Author(s): Kentaro Tojo, Nao Tamada, Yusuke Nagamine, Shuhei Ota, Takahisa Goto
  • Organizer: Euroanaesthesia 2017, The European Anesthesiology Congress
  • Int'l Joint Research
• [Presentation] Prolyl hydroxylase阻害は肺胞上皮細胞の代謝リプログラミングを介してLPS誘導性肺傷害を軽減する (2017)
  • Author(s): 東條 健太郎，玉田 尚，長嶺 祐介，矢澤 卓也，太田 周平，後藤 隆久
  • Organizer: 第６４回日本麻酔科学会総会
• [Presentation] Inhibition of Prolyl Hydroxylase Attenuates Fas Ligand-induced Apoptosis and Lung Injury in Mice (2016)
  • Author(s): Yusuke Nagamine, Kentaro Tojo, Takuya Yazawa, Shunsuke Takaki, Yasuko Baba, Takahisa Goto, Kiyoyasu Kurahashi
  • Organizer: ATS International Conference 2016
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2016-05-17
  • Int'l Joint Research
• [Presentation] The hydroxylase inhibitor dimethyloxallyl glycine protects lung epithelial barriers from LPS-induced injury in mice (2016)
  • Author(s): Kentaro Tojo
  • Organizer: Euroanaesthesia 2016
  • Place of Presentation: London, UK
  • Int'l Joint Research