PKR-dependent CHOP induction limits hyperoxia-induced lung injury
PKR-dependent CHOP induction limits hyperoxia-induced lung injury
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DOI：
10.1152/ajplung.00166.2010
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发表时间：
2011-03-01
影响因子：
4.9
通讯作者：
Altemeier, William A.
中科院分区：
文献类型：
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作者：
Lozon, Tricia I.;Eastman, Alison J.;Altemeier, William A.
Lozon TI、Eastman AJ、Matute-Bello G、Chen P、Hallstrand TS、Altemeier WA。 PKR 依赖性 CHOP 诱导可限制高氧引起的肺损伤。 Am J Physiol Lung Cell Mol Physiol 300：L422-L429，2011。首次发表于 2010 年 12 月 24 日； doi:10.1152/ajplung.00166.2010.-补充 O-2 通常用于呼吸衰竭患者；然而，高氧也是导致肺损伤的潜在因素。在动物模型中，高氧会导致肺部氧化应激，导致炎症、水肿和通透性增加。我们假设，长时间高氧引起的氧化应激会导致内质网（ER）应激，从而激活未折叠蛋白反应（UPR）并诱导CCAAT增强子结合蛋白同源蛋白（CHOP），这是一种在持续ER应激情况下与细胞死亡相关的转录因子。为了检验这一假设，我们将小鼠肺上皮细胞系 MLE-12 暴露于 95% O-2 中 8-24 小时，并评估 UPR 诱导和 CHOP 诱导的证据。高氧导致 CHOP 表达增加，但没有其他 UPR 激活的证据。由于 CHOP 表达之前是真核起始因子 2 (eIF2 α) α 亚基的磷酸化，因此我们评估了双链 RNA 激活蛋白激酶 (PKR)（一种非 UPR 相关 eIF2 α 激酶）的作用。高氧引起 PKR 磷酸化，RNA 干扰敲低 PKR 减弱高氧诱导的 CHOP 表达。在体内，高氧诱导肺部 PKR 磷酸化和 CHOP 表达，而没有其他 ER 应激的生化证据。此外，Ddit3(-/-)（CHOP-null）小鼠的肺水肿和通透性增加，表明长期高氧后 CHOP 具有以前未知的保护作用。我们得出的结论是，高氧通过一种不依赖于内质网应激、PKR 依赖的途径增加了 CHOP 的表达，并且增加的 CHOP 表达可以防止高氧引起的肺损伤。
Lozon TI, Eastman AJ, Matute-Bello G, Chen P, Hallstrand TS, Altemeier WA. PKR-dependent CHOP induction limits hyperoxia-induced lung injury. Am J Physiol Lung Cell Mol Physiol 300: L422-L429, 2011. First published December 24, 2010; doi:10.1152/ajplung.00166.2010.-Supplemental O-2 is commonly employed in patients with respiratory failure; however, hyperoxia is also a potential contributor to lung injury. In animal models, hyperoxia causes oxidative stress in the lungs, resulting in increased inflammation, edema, and permeability. We hypothesized that oxidative stress from prolonged hyperoxia leads to endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR) and induction of CCAAT enhancer-binding protein homologous protein (CHOP), a transcription factor associated with cell death in the setting of persistent ER stress. To test this hypothesis, we exposed the mouse lung epithelial cell line MLE-12 to 95% O-2 for 8-24 h and evaluated for evidence of UPR induction and CHOP induction. Hyperoxia caused increased CHOP expression without other evidence of UPR activation. Because CHOP expression is preceded by phosphorylation of the alpha-subunit of the eukaryotic initiation factor-2 (eIF2 alpha), we evaluated the role of double-stranded RNA-activated protein kinase (PKR), a non-UPR-associated eIF2 alpha kinase. Hyperoxia caused PKR phosphorylation, and RNA interference knockdown of PKR attenuated hyperoxia-induced CHOP expression. In vivo, hyperoxia induced PKR phosphorylation and CHOP expression in the lungs without other biochemical evidence for ER stress. Additionally, Ddit3(-/-) (CHOP-null) mice had increased lung edema and permeability, indicating a previously unknown protective role for CHOP after prolonged hyperoxia. We conclude that hyperoxia increases CHOP expression via an ER stress-independent, PKR-dependent pathway and that increased CHOP expression protects against hyperoxia-induced lung injury.