Silencing Angiopoietin-Like Protein 4 (ANGPTL4) Protects Against Lipopolysaccharide-Induced Acute Lung Injury Via Regulating SIRT1/NF-kB Pathway
Silencing Angiopoietin-Like Protein 4 (ANGPTL4) Protects Against Lipopolysaccharide-Induced Acute Lung Injury Via Regulating SIRT1/NF-kB Pathway
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DOI：
10.1002/jcp.24969
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发表时间：
2015-10-01
影响因子：
5.6
通讯作者：
Qian, Guisheng
中科院分区：
文献类型：
--
作者：
Guo, Liang;Li, Shaoying;Qian, Guisheng
肺部炎症和肺泡上皮细胞死亡是急性肺损伤（ALI）发生和进展的关键事件。尽管血管生成素样蛋白4（ANGPTL4）参与炎症，但其是否在ALI和肺泡上皮细胞炎症损伤中发挥重要作用仍不清楚。因此，我们研究了 angptl4 在脂多糖 (LPS) 诱导的 ALI 中的作用及其相关机制。将慢病毒介导的靶向小鼠 angptl4 基因的短干扰 RNA (AngsiRNA) 和阴性对照慢病毒 (NCsiRNA) 鼻内给予小鼠。随后确定了肺部炎症损伤以及 angptl4 对 LPS 诱导的 ALI 的调节作用的潜在机制。我们报道，在人肺泡上皮A549细胞和LPS诱导的ALI小鼠模型获得的肺组织中，angptl4水平均升高。LPS在肺泡上皮细胞中诱导Angptl4表达，而LPS诱导肺部炎症（肺组织中的中性粒细胞浸润、肿瘤坏死因子a、白细胞介素6）、肺通透性 AngsiRNA 治疗小鼠的肺湿/干重比和支气管肺泡灌洗液 (BALF) 蛋白浓度）、组织损伤（caspase3 激活）和死亡率均有所降低。 AngsiRNA(h)处理的A549细胞中炎症反应（肿瘤坏死因子a、白细胞介素6）和细胞凋亡率均降低。此外，angptl4 在小鼠肺和 A549 细胞中促进 NF-kBp65 表达并抑制 SIRT1 表达。此外，SIRT1 拮抗剂烟酰胺 (NAM) 减弱了 AngsiRNA 对 LPS 诱导的 NF-kBp65 表达和 IL6 表达的抑制作用。这些发现表明，沉默 angptl4 可通过调节 SIRT1/NF-kB 信号通路来预防 LPS 诱导的 ALI。 (C) 2015 年 Wiley 期刊公司。
Lung inflammation and alveolar epithelial cell death are critical events in the development and progression of acute lung injury (ALI). Although angiopoietin-like protein 4 (ANGPTL4) participates in inflammation, whether it plays important roles in ALI and alveolar epithelial cell inflammatory injury remains unclear. We therefore investigated the role of angptl4 in lipopolysaccharide (LPS)-induced ALI and the associated mechanisms. Lentivirus-mediated short interfering RNA targeted to the mouse angptl4 gene (AngsiRNA) and a negative control lentivirus (NCsiRNA) were intranasally administered to mice. Lung inflammatory injury and the underlying mechanisms for regulation of angptl4 on the LPS-induced ALI were subsequently determined. We reported that angptl4 levels were increased both in human alveolar epithelial A549 cells and lung tissues obtained from a mouse model of LPS-induced ALI.Angptl4 expression was induced by LPS in alveolar epithelial cells, whereas LPS-induced lung inflammation (neutrophils infiltration in the lung tissues, tumor necrosis factor a, interleukin 6), lung permeability (lung wet/dry weight ratio and bronchoalveolar lavage fluid (BALF) protein concentration), tissue damage (caspase3 activation), and mortality rates were attenuated in AngsiRNA-treated mice. The inflammatory reaction (tumor necrosis factor a, interleukin 6) and apoptosis rates were reduced in AngsiRNA(h)-treated A549 cells. Moreover, angptl4 promoted NF-kBp65 expression and suppressed SIRT1 expression both in mouse lungs and A549 cells. Additionally, SIRT1 antagonist nicotinamide (NAM) attenuated the inhibitory effects of AngsiRNA both on LPS-induced NF-kBp65 expression and IL6 expression. These findings suggest that silencing angptl4 protects against LPS-induced ALI via regulating SIRT1/NF-kB signaling pathway. (C) 2015 Wiley Periodicals, Inc.