Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model.
Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model.
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DOI：
10.1152/ajplung.00043.2016
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发表时间：
2016-12-01
期刊：
影响因子：
--
通讯作者：
Pinhu L
中科院分区：
文献类型：
--
作者：
Jiang Y;Zeng Y;Huang X;Qin Y;Luo W;Xiang S;Sooranna SR;Pinhu L
急性呼吸窘迫综合征（ARDS）的特征是肺泡和毛细血管屏障的炎性损伤，导致气体交换受损和严重的急性呼吸衰竭。核孤儿受体Nur 77已成为炎症中基因表达的调节因子，其在ARDS发病机制中的作用尚不清楚。本研究旨在探讨Nur 77在脂多糖（LPS）诱导的A549细胞和急性呼吸窘迫综合征（ARDS）大鼠模型中对内皮素-1（ET-1）表达的调节作用及其机制。我们证明LPS诱导A549细胞中Nur 77的表达和核输出。过表达Nur 77可显著降低A549细胞ET-1的基础表达和LPS诱导的ET-1表达，而敲低Nur 77则可增加ET-1的表达。LPS诱导的NF-κB和p38 MAPK磷酸化和核转位在A549细胞中被Nur 77过表达所阻断，而被Nur 77敲低所增强。在体内，LPS诱导ARDS大鼠肺组织Nur 77表达。CsnB（CsnB）对Nur 77的药理学激活可抑制ARDS大鼠ET-1的表达，降低LPS诱导的NF-κB和p38 MAPK的磷酸化，减轻肺、肝、肾损伤。1，1-二-（3′-吲哚基）-1-（对羟基苯基）甲烷（DIM-C-pPhOH，C-DIM 8）对Nur 77的药理学失活作用对ET-1表达和肺损伤无影响。这些结果表明Nur 77通过抑制NF-κB和p38 MAPK降低LPS刺激的A549细胞ET-1的表达; Csn B可降低LPS诱导的ARDS大鼠ET-1的表达，减轻肺损伤。
Acute respiratory distress syndrome (ARDS) is characterized by inflammatory injury to the alveolar and capillary barriers that results in impaired gas exchange and severe acute respiratory failure. Nuclear orphan receptor Nur77 has emerged as a regulator of gene expression in inflammation, and its role in the pathogenesis of ARDS is not clear. The objective of this study is to investigate the potential role of Nur77 and its underlying mechanism in the regulation of endothelin-1 (ET-1) expression in lipopolysaccharide (LPS)-induced A549 cells and an ARDS rat model. We demonstrate that LPS induced Nur77 expression and nuclear export in A549 cells. Overexpression of Nur77 markedly decreased basal and LPS-induced ET-1 expression in A549 cells, whereas knockdown of Nur77 increased the ET-1 expression. LPS-induced phosphorylation and nuclear translocation of NF-κB and p38 MAPK were blocked by Nur77 overexpression and augmented by Nur77 knockdown in A549 cells. In vivo, LPS induced Nur77 expression in lung in ARDS rats. Pharmacological activation of Nur77 by cytosporone B (CsnB) inhibited ET-1 expression in ARDS rats, decreased LPS-induced phosphorylation of NF-κB and p38 MAPK, and relieved lung, liver, and kidney injury. Pharmacological deactivation of Nur77 by 1,1-bis-(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH, C-DIM8) had no effect on ET-1 expression and lung injury. These results indicated that Nur77 decreases ET-1 expression by suppressing NF-κB and p38 MAPK in LPS-stimulated A549 cells in vitro, and, in an LPS-induced ARDS rat model, CsnB reduced ET-1 expression and lung injury in ARDS rats.
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影响因子：
5.8
作者：
Fagan KA;McMurtry IF;Rodman DM
通讯作者：
Rodman DM
影响因子：
20.1
作者：
Hamers, Anouk A. J.;Vos, Mariska;de Vries, Carlie J. M.
通讯作者：
de Vries, Carlie J. M.
影响因子：
1.7
作者：
Bhavsar, Tapan M.;Liu, Xingjian;Cantor, Jerome O.
通讯作者：
Cantor, Jerome O.
影响因子：
6.1
作者：
Caton, Paul W.;Nayuni, Nanda K.;Corder, Roger
通讯作者：
Corder, Roger
DOI：
10.1016/j.trsl.2009.02.007
发表时间：
2009-06
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
Comellas AP;Briva A
通讯作者：
Briva A