Tojo Kentaro, Tamada Nao, Nagamine Yusuke, Yazawa Takuya, Ota Shuhei, Goto Takahisa
Department of Anesthesiology and Critical Care Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
Department of Pathology, Dokkyo Medical University, Tochigi, Japan.
FASEB J. 2018 Apr;32(4):2258-2268. doi: 10.1096/fj.201700888R.
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-1α 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.- Tojo, K., Tamada, N., Nagamine, Y., Yazawa, T., Ota, S., Goto, T. Enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury. FASEB J. 32, 2258-2268 (2018). www.fasebj.org.
线粒体功能障碍引起的细胞生物能量衰竭是急性呼吸窘迫综合征（ARDS）期间肺泡上皮损伤的关键过程。脯氨酰羟化酶（PHD）作为细胞氧传感器，其抑制作用可激活缺氧诱导因子（HIF），从而增强细胞糖酵解活性，这可以补偿线粒体功能受损，并保护肺泡上皮细胞免受ARDS的影响。在此，我们使用体外和体内ARDS模型评估了用二甲基草酰甘氨酸（DMOG）进行药物性PHD抑制对肺泡上皮细胞损伤的影响。我们通过向培养的MLE12肺泡上皮细胞中添加分离的中性粒细胞和脂多糖（LPS），建立了一个模拟ARDS的肺泡上皮损伤体外模型。DMOG处理可保护MLE12细胞免受中性粒细胞-LPS诱导的ATP下降和细胞死亡。敲低HIF-1α或抑制糖酵解可消除DMOG的保护作用，表明其作用是通过HIF-1依赖性增强糖酵解来实现的。此外，对小鼠气管内给予DMOG可保护肺泡上皮屏障并改善动脉氧合，防止LPS诱导的肺损伤期间ATP下降。总之，通过抑制PHD增强糖酵解是一种潜在的ARDS治疗方法，可保护肺泡上皮细胞免受生物能量衰竭和细胞死亡。- Tojo, K., Tamada, N., Nagamine, Y., Yazawa, T., Ota, S., Goto, T. 抑制氧感应脯氨酰羟化酶增强糖酵解可保护肺泡上皮细胞免受急性肺损伤。《美国实验生物学会联合会杂志》32, 2258 - 2268 (2018)。www.fasebj.org 。
