Importance of pyruvate dehydrogenase in the mouse lungs exposed to hyperoxia

• Project/Area Number: 18K15729
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Saitama Medical University
• Principal Investigator: Kobayashi Shingo 埼玉医科大学, 医学部, 助教 (00464727)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 新生児慢性肺疾患 / 高濃度酸素 / ピルビン酸脱水素酵素 / メタボローム / 高濃度酸素性肺傷害 / 動物モデル / 解糖 / マウス

Outline of Final Research Achievements

This study investigated differences in the response to hyperoxic exposure between neonatal and adult mouse lungs using metabolomics analysis. Neonatal and adult mice were exposed to 21% or 95% O2 for four days. Lung tissue samples were collected and analyzed by metabolomics. Pyruvate dehydrogenase (PDH) enzyme activity, PDH kinase (Pdk) 4 mRNA expression levels, Pdk4 protein expression and localization were determined. Levels of pyruvic acid-related metabolites were elevated in the lungs of hyperoxia-exposed adult mice. PDH activity was reduced and Pdk4 mRNA expression levels after hyperoxic exposure were elevated in adult mice. Pdk4 protein levels were increased in adult mouse lungs exposed to hyperoxia and were localized mainly to the epithelium of terminal bronchiole.
Conclusions: Specific metabolites associated with glycolysis and gluconeogenesis were altered after hyperoxia exposure in the lungs of adult mice, but not in neonates.

Academic Significance and Societal Importance of the Research Achievements

新生仔マウスと成獣マウスの高濃度酸素暴露に対する耐性の違いについて、ピルビン酸代謝経路の違いで一部説明できることが示唆された。この結果から、将来的に、ピルビン酸代謝経路をターゲットとした新生児慢性肺疾患および成人呼吸窮迫症候群の治療法の開発が期待される。

Research Products

• [Journal Article] Difference in pyruvic acid metabolism between neonatal and adult mouse lungs exposed to hyperoxia (2020)
  • Author(s): Tanaka Kosuke、Watanabe Takaaki、Ozawa Junichi、Ito Masato、Nagano Nobuhiko、Arai Yukio、Miyake Fuyu、Matsumura Shun、Kobayashi Shingo、Itakura Ryuta、Namba Fumihiko
  • Journal Title: PLOS ONE Volume: 15 Issue: 9 Pages: 0238604-0238604
  • DOI: 10.1371/journal.pone.0238604
  • Peer Reviewed / Open Access
• [Presentation] Difference in lung pyruvic acid metabolism between neonatal and adult mice exposed to hyperoxia: a metabolomics approach (2019)
  • Author(s): Kosuke Tanaka, Junichi Ozawa, Takaaki Watanabe, Yukio Arai, Kikumi Matsuoka, Ryuta Itakura, Shingo Kobayashi, Masanori Tamura, Fumihiko Namba
  • Organizer: Pediatric Academic Societies Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] Difference in lung pyruvic acid metabolism between neonatal and adult mice exposed to hyperoxia: a metabolomics approach (2019)
  • Author(s): Tanaka K, Ozawa J, Watanabe T, Arai Y, Matsuoka K, Itakura R, Kobayashi S, Tamura M, Namba F
  • Organizer: Pediatric Academic Societies Annual Meeting
  • Int'l Joint Research
• [Presentation] Difference in pyruvic acid metabolism between neonatal and adult mouse lungs exposed to hyperoxia: a metabolomics approach (2018)
  • Author(s): Namba F, Tanaka K, Ozawa J, Watanabe T, Arai Y, Matsuoka K, Itakura R, Kobayashi S, Tamura M
  • Organizer: Pediatric Academic Societies Annual Meeting
  • Int'l Joint Research