Apelin-13 Attenuates Lipopolysaccharide-Induced Inflammatory Responses and Acute Lung Injury by Regulating PFKFB3-Driven Glycolysis Induced by NOX4-Dependent ROS.
Apelin-13 Attenuates Lipopolysaccharide-Induced Inflammatory Responses and Acute Lung Injury by Regulating PFKFB3-Driven Glycolysis Induced by NOX4-Dependent ROS.
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Apelin-13 通过调节 NOX4 依赖性 ROS 诱导的 PFKFB3 驱动的糖酵解来减轻脂多糖诱导的炎症反应和急性肺损伤
DOI：
10.2147/jir.s348850
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发表时间：
2022
影响因子：
4.5
通讯作者：
Meng Y
中科院分区：
文献类型：
--
作者：
Yuan Y;Wang W;Zhang Y;Hong Q;Huang W;Li L;Xie Z;Chen Y;Li X;Meng Y
目的急性肺损伤(ALI)是一种危及生命的疾病，治疗方法有限。巨噬细胞炎症在ALI的发生发展中起关键作用。巨噬细胞糖酵解异常导致炎症反应。然而，巨噬细胞糖酵解在ALI中的作用仍有待研究。Apelin-13已被证明对ALI有保护作用，但其潜在机制尚不清楚。在本研究中，我们通过调节巨噬细胞的氧化还原动态平衡来调节糖酵解，探讨apelin-13对内毒素诱导的炎症和ALI的影响。方法对34例脓毒症患者和13例健康志愿者的血清进行分析。在体内，采用脂多糖诱导的小鼠ALI模型，观察Apelin-13对脂多糖诱导的ALI的保护作用。在体外，小鼠骨髓巨噬细胞(BMDM)在暴露于脂多糖之前，用抗氧化剂NADPH氧化酶(NOX)4(NOX4)小干扰RNA(SiRNA)、6-磷酸果糖-2-激酶/果糖-2，6-双磷酸酶3(PFKFB3)siRNA或PFKFB3高表达质粒预处理。结果脓毒症及脓毒症相关性急性呼吸窘迫综合征患者血清apelin-13水平显著升高(P<；0.0001)。在体内，apelin-13抑制内毒素诱导的ALI和炎性细胞因子的产生(P<；0.05)。此外，apelin-13还降低了过氧化氢(H_2O_2)含量、NOX4蛋白水平和糖酵解。在体外，内毒素刺激增加了NOX4蛋白水平和活性氧(ROS)的产生(P<；0.05)。这些变化导致BMDM中糖酵解的积累。抗氧化剂或NOX4 siRNA可抑制内毒素诱导的糖酵解和炎性细胞因子的产生(P<；0.05)。此外，体外实验表明，PFKFB3通过调节糖酵解来调节促炎细胞因子的释放。相反，apelin-13的作用与内毒素的作用相反。结论Apelin-13通过调节依赖NOX4的ROS诱导的PFKFB3糖酵解，对内毒素诱导的炎症反应和ALI具有保护作用。
Purpose Acute lung injury (ALI) is a life-threatening condition with limited therapeutic options. Macrophage inflammation plays a key role in the development of ALI. Abnormal glycolysis of macrophages contributes to the inflammatory response. However, the role of macrophage glycolysis in ALI still requires investigation. Apelin-13 has been shown to protect against ALI, whereas the underlying mechanisms remain unclear. In this study, we explored the effect of apelin-13 on lipopolysaccharide (LPS)-induced inflammation and ALI via regulation of glycolysis by modulating redox homeostasis in macrophages. Methods Serums from 34 patients with sepsis and 13 healthy volunteers were analyzed. In vivo, the protective effect of apelin-13 against LPS-induced ALI was evaluated using a mouse model of LPS-induced ALI. In vitro, mouse bone marrow macrophages (BMDMs) were pretreated with the antioxidant, NADPH oxidase (NOX) 4 (NOX4) small-interfering RNA (siRNA), the 6-phosphofructo-2 -kinase/fructose- 2,6-biphosphatase 3 (PFKFB3) siRNA, or the PFKFB3 overexpression plasmid before exposure to LPS. Results Serum apelin-13 levels were significantly elevated in patients with sepsis and sepsis-associated acute respiratory distress syndrome (ARDS) (P<0.0001). In vivo, apelin-13 suppressed LPS-induced ALI and inflammatory cytokine production (P<0.05). Furthermore, apelin-13 reduced hydrogen peroxide (H2O2) content, NOX4 protein levels, and glycolysis. In vitro, LPS stimulation elevated NOX4 protein levels and reactive oxygen species (ROS) production (P<0.05). These changes resulted in the accumulation of glycolysis in BMDMs. Treatment with antioxidant or NOX4 siRNA inhibited LPS-induced glycolysis and inflammatory cytokine production (P<0.05). Moreover, in vitro experiments revealed that PFKFB3 regulates the release of pro-inflammatory cytokines by modulating glycolysis. In contrast, the action of apelin-13 opposed the effects of LPS. Conclusion In conclusion, apelin-13 protects against LPS-induced inflammatory responses and ALI by regulating PFKFB3-driven glycolysis induced by NOX4-dependent ROS.