Activation of the heat shock response attenuates the interleukin 1β-mediated inhibition of the amiloride-sensitive alveolar epithelial ion transport.
Activation of the heat shock response attenuates the interleukin 1β-mediated inhibition of the amiloride-sensitive alveolar epithelial ion transport.
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DOI：
10.1097/shk.0b013e31827e8ea3
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发表时间：
2013-02
期刊：
影响因子：
--
通讯作者：
Pittet JF
中科院分区：
文献类型：
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作者：
Howard M;Roux J;Iles KE;Miyazawa B;Christiaans S;Anjum N;Dickinson DA;Goolaerts A;Matthay MA;Pittet JF
急性肺损伤（Acute lung injury， ALI）是一种以肺泡毛细血管屏障破裂引起的缺氧为特征的临床综合征。IL-1β是ALI空域内释放的细胞因子，通过p38 MAP激酶依赖性信号通路下调αENaC转录和蛋白表达。虽然诱导热休克反应可以恢复大鼠严重失血性休克后被IL-1β破坏的肺泡液清除，但其机制尚不完全清楚。在本研究中，我们报道了热休克反应的诱导可阻止il -1β依赖性αENaC mRNA表达和随后通道功能的抑制。热休克导致IRAK1洗涤剂的不溶性和Hsp90与IRAK1结合的破坏。同样，热休克后，Hsp90的另一个客户蛋白TAK1和IL-1β通路的信号成分也是不溶性的。热休克24小时后，IRAK1和TAK1再次成为可溶清洁剂，这与il -1β依赖性p38激活相关。值得注意的是，热休克后24小时il -1β依赖的p38激活并未导致αENaC mRNA表达和通道功能的抑制。进一步的分析表明，通过激活诱导Hsp70的热休克反应，αENaC的表达得以延长。热休克后24小时抑制Hsp70可导致p38依赖性IL-1β抑制αENaC mRNA表达，而过表达Hsp70可减弱p38依赖性IL-1β对αENaC mRNA表达的抑制。这些研究揭示了急性肺损伤诱导热休克反应保护肺泡上皮屏障功能的新机制。
Acute lung injury (ALI) is a clinical syndrome characterized by hypoxia which is caused by the breakdown of the alveolar capillary barrier. IL-1β a cytokine released within the airspace in ALI, down-regulates αENaC transcription and protein expression via p38 MAP kinase-dependent signaling. While induction of the heat shock response can restore alveolar fluid clearance compromised by IL-1β following the onset of severe hemorrhagic shock in rats, the mechanisms are not fully understood. In this study, we report that the induction of the heat shock response prevents IL-1β-dependent inhibition of αENaC mRNA expression and subsequent channel function. Heat shock results in IRAK1 detergent insolubility and a disruption of Hsp90 binding to IRAK1. Likewise, TAK1, another client protein of Hsp90 and signaling component of the IL-1β pathway is also detergent insoluble after heat shock. Twenty-four hours post-heat shock, both IRAK1 and TAK1 are again detergent soluble, which correlates with the IL-1β-dependent p38 activation. Remarkably, IL-1β-dependent p38 activation 24-hour post-heat shock did not result in an inhibition of αENaC mRNA expression and channel function. Further analysis demonstrates prolonged preservation of αENaC expression by the activation of the heat shock response that involves inducible Hsp70. Inhibition of Hsp70 at 24 hours post-heat shock results in p38-dependent IL-1β inhibition of αENaC mRNA expression while over-expression of Hsp70 attenuates the p38-dependent IL-1β inhibition of αENaC mRNA expression. These studies demonstrate new mechanisms by which the induction of the heat shock response protects the barrier function of the alveolar epithelium in acute lung injury.