Inhibition of glycolysis alleviates lipopolysaccharide-induced acute lung injury in a mouse model
Inhibition of glycolysis alleviates lipopolysaccharide-induced acute lung injury in a mouse model
复制标题
抑制糖酵解可减轻小鼠模型中脂多糖诱导的急性肺损伤
DOI：
10.1002/jcp.27261
复制
发表时间：
2019-04-01
影响因子：
5.6
通讯作者：
Guan, Cha-Xiang
中科院分区：
文献类型：
--
作者：
Zhong, Wen-Jing;Yang, Hui-Hui;Guan, Cha-Xiang
葡萄糖代谢重编程、免疫反应和炎症密切相关。糖酵解参与了急、慢性炎症性疾病的病理过程。然而，糖酵解在急性肺损伤（ALI）中的作用尚不清楚。本研究探讨了糖酵解在ALI动物模型中的作用。首先，我们发现在ALI患者和内毒素（LPS）诱导的小鼠模型中，血清乳酸含量显著升高。参与糖酵解的关键蛋白质显著升高，包括HK 2、PKM 2和HIF-1。2-脱氧葡萄糖（2-DG）抑制糖酵解可明显减轻LPS诱导的ALI小鼠肺组织病理损伤、中性粒细胞聚集、氧化应激和促炎因子表达。2-DG处理还强烈抑制了NOD样受体（NLR）家族和含pyrin结构域蛋白3（NLRP 3）炎性体的活化。此外，我们研究了糖酵解在体外LPS激活的原代小鼠巨噬细胞炎症反应中的作用。结果表明，2-DG能显著降低LPS诱导的促炎因子的表达，包括肿瘤坏死因子-信使RNA（mRNA）、白细胞介素（IL）-1mRNA、IL-18 mRNA、NLRP 3 mRNA、caspase-1 mRNA和IL-1蛋白。总之，这些数据提供了一种新的链接之间的葡萄糖代谢重编程和不受控制的炎症反应在ALI。本研究提示糖酵解抑制是治疗ALI的有效抗炎策略。
Gluconic metabolic reprogramming, immune response, and inflammation are intimately linked. Glycolysis involves in the pathologic progress in acute and chronic inflammatory diseases. However, the involvement of glycolysis in the acute lung injury (ALI) is still unclear. This study investigated the role of glycolysis in an animal model of ALI. First, we found that lactate content in serum was remarkably increased in ALI patients and a murine model induced by intratracheal administration of lipopolysaccharide (LPS). The key proteins involving in glycolysis were robustly elevated, including HK2, PKM2, and HIF-1. Intriguingly, inhibition of glycolysis by 2-deoxyglucose (2-DG) pronouncedly attenuated the lung tissue pathological injury, accumulation of neutrophil, oxidative stress, expression of proinflammatory factors in the lung of ALI mice induced by LPS. The 2-DG treatment also strongly suppressed the activation of the NOD-like receptor (NLR) family and pyrin domain-containing protein 3 (NLRP3) inflammasome. Furthermore, we investigated the role of glycolysis in the inflammatory response of primary murine macrophages activated by LPS in vitro. We found that the 2-DG treatment remarkably reduced the expression of proinflammatory factors induced by LPS, including tumor necrosis factor- messenger RNA (mRNA), pro-interleukin (IL)-1 mRNA, pro-IL-18 mRNA, NLRP3 mRNA, caspase-1 mRNA, and IL-1 protein. Altogether, these data provide a novel link between gluconic metabolism reprogramming and uncontrolled inflammatory response in ALI. This study suggests glycolytic inhibition as an effective anti-inflammatory strategy in treating ALI.