The role of cellular redox system in inflammatory disorders of acute lung injury

• Project/Area Number: 15K10551
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Anesthesiology
• Research Institution: The Tazuke Kofukai
• Principal Investigator: ADACHI Takehiko 公益財団法人田附興風会, 医学研究所 第9研究部, 部長 (90252428)
• Co-Investigator(Kenkyū-buntansha): 広田 喜一 関西医科大学, 医学部, 教授 (00283606)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 酸素環境 / 敗血症 / 急性肺障害 / thioredoxin / TXNIP / HIF-1 / 低酸素誘導性因子1 / 急性肺傷害

Outline of Final Research Achievements

The aim of this study is to evaluate the clinical significance of the cellular redox system consisting of thioredoxin and thioredoxin interacting protein (Txnip) for the protection against inflammatory disorders including septi shock, ALI, and ARDS. Since inflammation has been associated with hypoxia and the resulting dysregulation of oxygen homeostasis, we investigated the functional interaction between the thioredoxin system and hypoxia-inducible factor 1 (HIF-1) under inflammatory conditions. We showed that thioredoxin enhanced the transcriptional activity of HIF-1. Thioredoxin-induced HIF-1 activation up-regulated the expression level of Txnip, which could, in turn, suppress the function of thioredoxin. These results revealed that the cellular redox environment was maintained by a subtle balance and interplay between these redox-related molecules.

Research Products

• [Journal Article] Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner (2018)
  • 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 Issue: 2 Pages: e0192796-e0192796
  • DOI: 10.1371/journal.pone.0192796
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cigarette smoke reversibly activates hypoxia-inducible factor 1 in a reactive oxygen species-dependent manner (2016)
  • Author(s): Daijo H, Hoshino Y, Kai S, Suzuki K, Nishi K, Matsuo Y, Harada H, Hirota K
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 34424-34424
  • DOI: 10.1038/srep34424
  • NAID: 120005850269
  • Peer Reviewed / Open Access
• [Journal Article] The antioxidant N-acetyl cysteine suppresses lidocaine-induced intracellular reactive oxygen species production and cell death in neuronal SH-SY5Y cells (2016)
  • 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 Anesthesiol Volume: 16 Issue: 1 Pages: 104-104
  • DOI: 10.1186/s12871-016-0273-3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] VHL-deficient renal cancer cells gain resistance to mitochondria-activating apoptosis inducers by activating AKT through the IGF1R-PI3K pathway (2016)
  • Author(s): Yamaguchi R, Harada H, Hirota K
  • Journal Title: Tumor Biology Volume: 37 Issue: 10 Pages: 13295-13306
  • DOI: 10.1007/s13277-016-5260-2
  • Peer Reviewed / Open Access
• [Journal Article] UCHL1 provides diagnostic and antimetastatic strategies due to its deubiquitinating effect on HIF-1alpha (2015)
  • Author(s): Goto Y, Zeng L, YeomCJ, Zhu Y, Morinibu A, Shinoyam K, Kobayashi M, Hirota K, Itasaka S, Yoshimura M, Tanimoto K, Sowa T, Menju T, Sonobe M, Kakeya H, Toi M, Date H, Hammond EM, Hiraoka M, Harada H.
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 1-10
  • DOI: 10.1038/ncomms7153
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of hypozia-inducible factors in the dysregulation of oxygen homeostasis in sepsis (2015)
  • Author(s): Hirota K.
  • Journal Title: Cardiovascular & hematological disorders drug targets Volume: 15 Issue: 1 Pages: 29-40
  • DOI: 10.2174/1871529x15666150108115553
  • Peer Reviewed / Open Access
• [Journal Article] Volatile anesthetics suppress glucose-stimulated insulin secretion in MIN6 cells by inhibiting glucose-induced activation of hypoxia-inducible factor 1. (2015)
  • Author(s): Suzuki K, Sato Y, Kai S, Nishi K, Adachi T, Matsuo Y, Hirota K.
  • Journal Title: PeerJ. Volume: 3 Pages: 1498-1498
  • DOI: 10.7717/peerj.1498
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] HIF-1-Mediated Suppression of Mitochondria Electron Transport Chain Function Confers _Resistance to Lidocaine-induced Cell Death (2017)
  • Author(s): SHINICHI KAI, Kiichi Hirota, Chisato Sumi, Akihisa Okamoto, Kenichiro Nishi, Munenori Kusunoki, Yoshiyuki Matsuo, Takehiko Adachi
  • Organizer: American Society of Anesthesiology 2017 annual meeting
  • Int'l Joint Research
• [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: コラッセふくしま（福島市）