Hypoxia Exacerbates Inflammatory Acute Lung Injury via the Toll-Like Receptor 4 Signaling Pathway.
Hypoxia Exacerbates Inflammatory Acute Lung Injury via the Toll-Like Receptor 4 Signaling Pathway.
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缺氧通过 Toll 样受体 4 信号通路加剧炎症性急性肺损伤
DOI：
10.3389/fimmu.2018.01667
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发表时间：
2018
影响因子：
7.3
通讯作者：
Gao YQ
中科院分区：
文献类型：
--
作者：
Wu G;Xu G;Chen DW;Gao WX;Xiong JQ;Shen HY;Gao YQ
急性肺损伤（acute lung injury，ALI）是一种以非心源性弥漫性肺泡损伤为特征的肺损伤，常导致死亡，尤其是在缺氧共存时。ALI的治疗仍然是一个挑战：肺部炎症和缺氧都有助于其发病和进展，并且没有有效的预防方法。本研究旨在探讨ALI中缺氧与炎症相互作用的机制，并评估缺氧诱导因子1 α（HIF-1α）--缺氧中的关键调节因子--作为治疗ALI的潜在靶点。首先，我们建立了低剂量脂多糖（LPS）联合急性缺氧诱导的大鼠ALI模型。第二，我们利用基因芯片技术分析了ALI大鼠支气管肺泡灌洗液细胞的炎症特征。第三，我们采用肺泡巨噬细胞系NR 8383作为体外系统，与toll样受体4（TLR 4）拮抗剂TAK-242一起，以验证我们在ALI动物体内的发现。最后，我们测试了HIF-1α增强对ALI中炎症和缺氧的治疗作用。结果表明：（1）LPS上调了ALI大鼠肺泡巨噬细胞中的炎症基因TNF-α、IL-1 β和IL-6，且在ALI合并缺氧时进一步增强;（ii）低氧暴露可进一步增强LPS诱导的炎性ALI中肺泡巨噬细胞TLR 4的上调，相反，TLR 4拮抗剂TAK-242可抑制巨噬细胞TLR 4和炎性细胞因子TNF-α、IL-1β、IL-6的表达，提示TLR 4信号通路是ALI炎症和缺氧之间的中心环节：（iii）体外操作HIF-1α可通过抑制TLR 4基因启动子活性抑制LPS和缺氧联合诱导的TLR 4表达;（iv）HIF-1α羟化酶抑制剂在体内预处理增强HIF-1α的表达，DMOG分泌对ALI炎症和缺氧过程的保护作用。总之，我们看到缺氧可以通过激活肺泡巨噬细胞中的TLR 4信号通路来加剧ALI中的炎症，并在ALI的发展中使肺泡毛细血管屏障受损。靶向HIF-1α可抑制TLR 4的表达和巨噬细胞炎症反应，提示HIF-1α/TLR 4信号通路在ALI中具有潜在的治疗和预防价值。
Acute lung injury (ALI) is characterized by non-cardiogenic diffuse alveolar damage and often leads to a lethal consequence, particularly when hypoxia coexists. The treatment of ALI remains a challenge: pulmonary inflammation and hypoxia both contribute to its onset and progression and no effective prevention approach is available. Here, we aimed to investigate the underlying mechanism of hypoxia interaction with inflammation in ALI and to evaluate hypoxia-inducible factor 1 alpha (HIF-1α)—the crucial modulator in hypoxia—as a potential therapeutic target against ALI. First, we developed a novel ALI rat model induced by a combined low-dose of lipopolysaccharides (LPS) with acute hypoxia. Second, we used gene microarray analysis to evaluate the inflammatory profiles of bronchi alveolar lavage fluid cells of ALI rats. Third, we employed an alveolar macrophage cell line, NR8383 as an in vitro system together with a toll-like receptor 4 (TLR4) antagonist TAK-242, to verify our in vivo findings from ALI animals. Finally, we tested the therapeutic effects of HIF-1α augmentation against inflammation and hypoxia in ALI. We demonstrated that (i) LPS upregulated inflammatory genes, tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), in the alveolar macrophages of ALI rats, which were further enhanced when ALI combined with hypoxia; (ii) hypoxia exposure could further enhance the upregulation of alveolar macrophageal TLR4 that was noticed in LPS-induced inflammatory ALI, conversely, TLR4 antagonist TAK-242 could suppress the macrophageal expression of TLR4 and inflammatory cytokines, including TNF-α, IL-1β, and IL-6, suggesting that the TLR4 signaling pathway as a central link between inflammation and hypoxia in ALI; (iii) manipulation of HIF-1α in vitro could suppress TLR4 expression induced by combined LPS and hypoxia, via suppressing promoter activity of the TLR4 gene; (iv) preconditioning augmentation of HIF-1α in vivo by HIF hydroxylase inhibitor, DMOG excreted protection against inflammatory, and hypoxic processes in ALI. Together, we see that hypoxia can exacerbate inflammation in ALI via the activation of the TLR4 signaling pathway in alveolar macrophages and predispose impairment of the alveolar-capillary barrier in the development of ALI. Targeting HIF-1α can suppress TLR4 expression and macrophageal inflammation, suggesting the potential therapeutic and preventative value of HIF-1α/TLR4 crosstalk pathway in ALI.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
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影响因子：
4.6
作者：
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