Enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury

Tojo Kentaro; Tamada Nao; Nagamine YusukeYazawa TakuyaOta ShuheiGoto Takahisa

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Enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury

机译：Enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury

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Cellular bioenergetic failure caused by mitochondrial dysfunction is a key process of alveolar epithelial injury during acute respiratory distress syndrome (ARDS). Prolyl hydroxylases (PHDs) act as cellular oxygen sensors, and their inhibition activates hypoxia-inducible factor (HIF), resulting in enhanced cellular glycolytic activity, which could compensate for impaired mitochondrial function and protect alveolar epithelial cells from ARDS. Here, we evaluated the effects of pharmacological PHD inhibition with dimethyloxalylglycine (DMOG) on alveolar epithelial cell injury using in vitro and in vivo ARDS models. We established an in vitro model of alveolar epithelial injury mimicking ARDS by adding isolated neutrophils and LPS to cultured MLE12 alveolar epithelial cells. DMOG treatment protected MLE12 cells from neutrophil-LPS-induced ATP decline and cell death. Knockdown of HIF-1 alpha or inhibition of glycolysis abolished the protective effect of DMOG, suggesting that it was exerted by HIF-1-dependent enhancement of glycolysis. Additionally, intratracheal DMOG administration to mice protected the alveolar epithelial barrier and improved arterial oxygenation, preventing ATP decline during LPS-induced lung injury. In summary, enhancement of glycolysis by PHD inhibition is a potential therapeutic approach for ARDS, protecting alveolar epithelial cells from bioenergetic failure and cell death.

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来源
《The FASEB Journal》 |2018年第4期|2258-2268|共11页
作者
Tojo Kentaro; Tamada Nao; Nagamine YusukeYazawa TakuyaOta ShuheiGoto Takahisa;
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作者单位

Yokohama City Univ, Grad Sch Med, Dept Anesthesiol & Crit Care Med, Yokohama, Kanagawa, Japan;

Dokkyo Med Univ, Dept Pathol, Mibu, Tochigi, Japan;

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原文格式 PDF
正文语种英语
中图分类生物化学;
关键词
ARDS; energy metabolism; prolyl-hydroxylase inhibitors; hypoxia-inducible factor 1; cell death;

Enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury

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