PI3K-AKT Signaling via Nrf2 Protects against Hyperoxia-Induced Acute Lung Injury, but Promotes Inflammation Post-Injury Independent of Nrf2 in Mice.
PI3K-AKT Signaling via Nrf2 Protects against Hyperoxia-Induced Acute Lung Injury, but Promotes Inflammation Post-Injury Independent of Nrf2 in Mice.
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DOI：
10.1371/journal.pone.0129676
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Reddy SP
中科院分区：
文献类型：
--
作者：
Reddy NM;Potteti HR;Vegiraju S;Chen HJ;Tamatam CM;Reddy SP
肺上皮细胞和内皮细胞死亡伴随炎症反应是高氧诱导的急性肺损伤（ALI）的重要原因。ALI的消退受损可促进和/或延续肺发病机制，包括纤维化。以前，我们已经表明，转录因子Nrf 2诱导细胞保护基因的表达，并赋予对高氧肺损伤的保护，Nrf 2介导的信号传导也是至关重要的肺损伤后的稳态恢复。虽然我们已经报道了肺上皮细胞中Nrf 2激活需要PI 3 K/AKT信号传导，但是在高氧肺损伤和修复期间PI 3 K/AKT-Nrf 2串扰的意义仍然不清楚。因此，我们使用Nrf 2敲除（Nrf 2-/-）和野生型（Nrf 2 +/+）小鼠模型评估了这方面。在这里，我们发现，药物抑制PI 3 K/AKT信号增加了Nrf 2 +/+小鼠的肺部炎症和肺泡通透性，同时降低了Nrf 2靶基因如Nqo 1和Hmox 1的表达。PI 3 K/AKT抑制抑制了肺上皮细胞和肺泡巨噬细胞中高氧刺激的Nqo 1和Hmox 1表达。与其保护作用相比，PI 3 K/AKT抑制抑制Nrf 2 +/+小鼠在损伤后的肺部炎症。在暴露于室内空气的Nrf 2-/-小鼠中，PI 3 K/AKT抑制引起肺损伤和炎症，但它并没有加重高氧诱导的ALI。在损伤后，PI 3 K/AKT抑制并没有增加，而是减弱了Nrf 2-/-小鼠的肺部炎症。这些结果表明，PI 3 K/AKT-Nrf 2信号传导是抑制高氧诱导的肺损伤和炎症所必需的。有趣的是，在损伤后，PI 3 K/AKT通路促进肺部炎症，独立于Nrf 2。
Lung epithelial and endothelial cell death accompanied by inflammation contributes to hyperoxia-induced acute lung injury (ALI). Impaired resolution of ALI can promote and/or perpetuate lung pathogenesis, including fibrosis. Previously, we have shown that the transcription factor Nrf2 induces cytoprotective gene expression and confers protection against hyperoxic lung injury, and that Nrf2-mediated signaling is also crucial for the restoration of lung homeostasis post-injury. Although we have reported that PI3K/AKT signaling is required for Nrf2 activation in lung epithelial cells, significance of the PI3K/AKT-Nrf2 crosstalk during hyperoxic lung injury and repair remains unclear. Thus, we evaluated this aspect using Nrf2 knockout (Nrf2 –/–) and wild-type (Nrf2 +/+) mouse models. Here, we show that pharmacologic inhibition of PI3K/AKT signaling increased lung inflammation and alveolar permeability in Nrf2 +/+ mice, accompanied by decreased expression of Nrf2-target genes such as Nqo1 and Hmox1. PI3K/AKT inhibition dampened hyperoxia-stimulated Nqo1 and Hmox1 expression in lung epithelial cells and alveolar macrophages. Contrasting with its protective effects, PI3K/AKT inhibition suppressed lung inflammation in Nrf2 +/+ mice during post-injury. In Nrf2 –/– mice exposed to room-air, PI3K/AKT inhibition caused lung injury and inflammation, but it did not exaggerate hyperoxia-induced ALI. During post-injury, PI3K/AKT inhibition did not augment, but rather attenuated, lung inflammation in Nrf2 –/– mice. These results suggest that PI3K/AKT-Nrf2 signaling is required to dampen hyperoxia-induced lung injury and inflammation. Paradoxically, the PI3K/AKT pathway promotes lung inflammation, independent of Nrf2, during post-injury.
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影响因子：
7.4
作者：
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通讯作者：
White，CW
影响因子：
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作者：
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DOI：
10.1196/annals.1299.074
发表时间：
2003-01-01
期刊：
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影响因子：
--
作者：
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通讯作者：
Barazzone-Argiroffo, C
DOI：
10.1152/ajprenal.00421.2009
发表时间：
2010-03-01
影响因子：
4.2
作者：
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通讯作者：
Vaziri, Nosratola D.
DOI：
10.1152/ajplung.00179.2005
发表时间：
2005-12-01
影响因子：
4.9
作者：
Ong, E;Gao, XP;Malik, AB
通讯作者：
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