Evaluation of PFKFB3 inhibition in neonatal mice with LPS-induced acute lung injury

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17330
• 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: Kobe University
• Principal Investigator: Ikuta Toshihiko 神戸大学, 医学部附属病院, 医学研究員 (40814588)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: PFKFB3 / glycolysis / acute lung injury / endothelial cells / neonatal mouse

Outline of Final Research Achievements

Acute lung injury (ALI) in neonates is strongly related to the dysfunction of pulmonary vascular endothelial cells in which the cellular metabolism is highly dependent on glycolysis, particularly regulated by 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). We evaluated the effects of pharmacological PFKFB3 inhibition in a neonatal mouse model of lipopolysaccharide (LPS)-induced ALI and in LPS-treated human pulmonary artery endothelial cells (HPAEC). Inhibition of PFKFB3 exacerbates LPS-induced ALI with heightened vascular permeability in neonatal mice, and suppressed gene expression of adhesion molecules, especially Claudin1, a tight junction-related molecule in LPS-treated HPAEC. This suggests that the upregulation of PFKFB3 in response to inflammatory stimulus might play a crucial role to maintain the integrity of HPAEC and is protective in neonatal ALI through preserving pulmonary vascular barrier function.

Free Research Field

新生児学

Academic Significance and Societal Importance of the Research Achievements

新生児急性肺障害は高度な炎症と続発するサーファクタント欠乏を特徴とする肺障害と定義されているが、病態解明は不十分であり、特異的な治療法も少ない。本研究では、解糖系律速酵素であるPFKFB3が新生仔マウスを用いたLPS誘導性肺障害モデルにおける肺血管バリア機能の維持に重要であり、PFKFB3阻害が細胞間接着因子、特にtight junction関連分子であるcalaudin 1の遺伝子発現を抑制することを明らかにした。本研究の結果は、PFKFB3が新生急性肺障害の治療標的や予後予測因子となり得ることを示唆するものであり、その学術的意義は大きい。