Blockage of glycolysis by targeting PFKFB3 alleviates sepsis-related acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells
Blockage of glycolysis by targeting PFKFB3 alleviates sepsis-related acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells
复制标题
DOI：
10.1016/j.bbrc.2017.05.173
复制
发表时间：
2017-09-16
影响因子：
3.1
通讯作者：
Shao, Jianghua
中科院分区：
文献类型：
--
作者：
Gong, Yuanqi;Lan, Haibing;Shao, Jianghua
脓毒症相关的急性肺损伤（ALI）的特征是过度的肺部炎症和肺泡上皮细胞凋亡，导致急性低氧性呼吸衰竭。最近的研究表明无氧糖酵解在脓毒症中发挥重要作用。然而，抑制有氧糖酵解是否对脓毒症诱发的 ALI 具有有益作用尚不清楚。在体内，建立盲肠结扎穿刺（CLP）诱导的ALI小鼠模型，并在CLP后用糖酵解抑制剂3PO治疗小鼠。用3PO治疗的小鼠改善了CLP诱导的败血症小鼠的存活率、组织病理学变化、肺部炎症、乳酸增加和肺细胞凋亡。在体外，人肺泡上皮 A549 细胞暴露于脂多糖 (LPS) 会导致细胞凋亡、炎症细胞因子产生、糖酵解通量增加和活性氧 (ROS) 增加。而这些变化通过 3PO 处理而减弱。随后，用乳酸处理 A549 细胞引起细胞凋亡和 ROS 增强。 N-乙酰半胱氨酸 (NAC) 预处理显着降低 A549 细胞中的 LPS 和乳酸诱导 ROS 的产生和细胞凋亡。因此，这些结果表明无氧糖酵解可能是脓毒症相关ALI细胞凋亡的重要贡献者。此外，LPS 通过乳酸介导的 ROS 增强，特异性诱导 A549 细胞凋亡。 (C) 2017 Elsevier Inc. 保留所有权利。
Sepsis-related acute lung injury (ALI) is characterized by excessive lung inflammation and apoptosis of alveolar epithelial cells resulting in acute hypoxemic respiratory failure. Recent studies indicated that anaerobic glycolysis play an important role in sepsis. However, whether inhibition of aerobic glycolysis exhibits beneficial effect on sepsis-induced ALI is not known. In vivo, a cecal ligation and puncture (CLP)-induced ALI mouse model was set up and mice treated with glycolytic inhibitor 3PO after CLP. The mice treated with the 3PO ameliorated the survival rate, histopathological changes, lung inflammation, lactate increased and lung apoptosis of mice with CLP-induced sepsis. In vitro, the exposure of human alveolar epithelial A549 cells to lipopolysaccharide (LPS) resulted in cell apoptosis, inflammatory cytokine production, enhanced glycolytic flux and reactive oxygen species (ROS) increased. While these changes were attenuated by 3PO treatment. Sequentially, treatment of A549 cells with lactate caused cell apoptosis and enhancement of ROS. Pretreatment with N-acetylcysteine (NAC) significantly lowered LPS and lactate induced the generation of ROS and cell apoptosis in A549 cells. Therefore, these results indicate that anaerobic glycolysis may be an important contributor in cell apoptosis of sepsis-related ALI. Moreover, LPS specifically induces apoptotic insults to A549 cell through lactate-mediated enhancement of ROS. (C) 2017 Elsevier Inc. All rights reserved.