4-PBA inhibits LPS-induced inflammation through regulating ER stress and autophagy in acute lung injury models
4-PBA inhibits LPS-induced inflammation through regulating ER stress and autophagy in acute lung injury models
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DOI：
10.1016/j.toxlet.2017.02.023
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发表时间：
2017-04-05
影响因子：
3.5
通讯作者：
Kong, Xiaoxia
中科院分区：
文献类型：
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作者：
Zeng, Meichun;Sang, Wenhua;Kong, Xiaoxia
急性肺损伤（ALI）是一种常见的临床疾病，在世界范围内引起严重的健康问题。过度的炎症反应是ALI的核心特征，但其机制尚不清楚，尤其是内质网应激和自噬的作用。为了探讨脂多糖（LPS）诱导的小鼠ALI模型中肺部炎症的细胞机制，我们研究了经典的ER应激抑制剂4-苯基丁酸（4-PBA）对LPS诱导的ALI小鼠模型和人肺泡上皮细胞模型中ER应激和自噬的影响。我们证明，4-PBA进一步阻止了NF-κ B通路的激活，减少了促炎介质IL-1 β、TNF-α和IL-6的释放，显著抑制了LPS激活的ER应激。此外，还发现4-PBA处理也降低了自噬，这可能通过经典的AKT/mTOR信号通路在ALI模型中发挥保护作用。通过3-MA抑制自噬加剧LPS诱导的A549肺泡上皮细胞的细胞毒性。综上所述，我们的研究表明内质网应激是LPS诱导的炎症反应的关键启动子，4-PBA的保护作用与抑制内质网应激和自噬有关。此外，有助于细胞存活的自噬作用可能取决于ER应激的激活。(C)2017爱思唯尔B. V.保留所有权利。
Acute lung injury (ALI) is a common clinical disorder that causes substantial health problems worldwide. An excessive inflammatory response is the central feature of ALI, but the mechanism is still unclear, especially the role of endoplasmic-reticulum (ER) stress and autophagy. To identify the cellular mechanism of lung inflammation during lipopolysaccharide (LPS)-induced mouse model of ALI, we investigated the influence of classic ER stress inhibitor 4-phenyl butyric acid (4-PBA) on ER stress and autophagy, which partially affect the activation of inflammation, both in LPS-induced ALI mouse model and human alveolar epithelial cell model. We demonstrated that 4-PBA, which further prevented the activation of the NF-kB pathway, decreased the release of the pro- inflammatory mediators IL-1 beta, TNF-alpha and IL-6, significantly inhibited LPS-activated ER stress. Moreover, it was found that autophagy was also decreased by the treatment of 4-PBA, which may play a protective role in ALI models through the classical AKT/mTOR signaling pathway. Inhibition of autophagy by 3-MA exacerbates cytotoxicity induced by LPS in A549 alveolar epithelial cells. Taken together, our study indicated that ER stress is a key promoter in the induction of inflammation by LPS, the protective effect of 4-PBA is related to the inhibition of ER stress and autophagy in LPS-induced ALI models. Furthermore, the role of autophagy that contributes to cell survival may depend on the activation of ER stress. (C) 2017 Elsevier B.V. All rights reserved.