Glutathione reductase deficiency alters lung development and hyperoxic responses in neonatal mice.
Glutathione reductase deficiency alters lung development and hyperoxic responses in neonatal mice.
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DOI：
10.1016/j.redox.2020.101797
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发表时间：
2021-01
期刊：
影响因子：
11.4
通讯作者：
Tipple TE
中科院分区：
文献类型：
--
作者：
Robbins ME;Cho HY;Hansen JM;Luchsinger JR;Locy ML;Velten M;Kleeberger SR;Rogers LK;Tipple TE
细胞抗氧化剂防止高氧肺损伤。谷胱甘肽（GSH）系统在肺发育和支气管肺发育不良（BPD）发病机制中的作用尚未得到系统研究。目前的研究利用GSH还原酶缺陷（Gsr-KO）新生小鼠来检验GSH系统的早期破坏对肺发育和高氧反应产生负面影响的假设。在暴露于室内空气或高氧（85%O2）长达14 d后，分析野生型（Gsr-WT）和Gsr-KO小鼠肺的组织病理学、发育标志物、氧化还原指数和不同发育阶段的转录组谱。来自Gsr-KO小鼠的肺在胚胎期和新生儿期表现出肺泡上皮发育不良，在成年期具有相对正常的肺结构。在E19-PND 14，Gsr-KO肺中GSH及其氧化形式（GSSG）比年龄匹配的Gsr-WT低50-70%。在离散的发育阶段分析Gsr-WT和Gsr-KO肺之间的差异基因表达。Gsr-KO肺在E19表现出下调的细胞周期和DNA损伤检查点基因，以及在PND 5表现出下调的肺脂质代谢和表面活性剂基因。除了基线肺形态测量异常外，Gsr-KO小鼠对高氧反应迟钝。与Gsr-WT相比，高氧导致Gsr-KO中肺硫氧还蛋白系统的更稳健的上调。GSr依赖性、高氧反应基因与PND 5时异常的细胞骨架、骨骼肌肉功能和组织形态高度相关。总的来说，我们在Gsr-KO小鼠中的数据表明GSH系统是新生小鼠肺发育、细胞分化和高氧反应的关键调节因子。谷氨酰胺还原酶缺乏改变新生儿期肺发育。硫氧还蛋白系统补偿谷胱甘肽还原酶缺乏。谷胱甘肽还原酶缺乏导致转录组显著差异。肺结构和转录组在成年期正常化。谷胱甘肽还原酶缺乏比氧缺乏差异表达的基因更多。
Cellular antioxidants protect against hyperoxic lung injury. The role of the glutathione (GSH) system in lung development and bronchopulmonary dysplasia (BPD) pathogenesis has not been systematically investigated. The current study utilized GSH reductase-deficient (Gsr-KO) neonatal mice to test the hypothesis that early disruption of the GSH system negatively impacts lung development and hyperoxic responses. Lungs from wild-type (Gsr-WT) and Gsr-KO mice were analyzed for histopathology, developmental markers, redox indices, and transcriptome profiling at different developmental stages following exposure to room air or hyperoxia (85% O2) for up to 14 d. Lungs from Gsr-KO mice exhibited alveolar epithelial dysplasia in the embryonic and neonatal periods with relatively normal lung architecture in adulthood. GSH and its oxidized form (GSSG) were 50–70% lower at E19-PND14 in Gsr-KO lungs than in age-matched Gsr-WT. Differential gene expression between Gsr-WT and Gsr-KO lungs was analyzed at discrete developmental stages. Gsr-KO lungs exhibited downregulated cell cycle and DNA damage checkpoint genes at E19, as well as lung lipid metabolism and surfactant genes at PND5. In addition to abnormal baseline lung morphometry, Gsr-KO mice displayed a blunted response to hyperoxia. Hyperoxia caused a more robust upregulation of the lung thioredoxin system in Gsr-KO compared to Gsr-WT. Gsr-dependent, hyperoxia-responsive genes were highly associated with abnormal cytoskeleton, skeletal-muscular function, and tissue morphology at PND5. Overall, our data in Gsr-KO mice implicate the GSH system as a key regulator of lung development, cellular differentiation, and hyperoxic responses in neonatal mice. Glutathione reductase deficiency alters lung development in the neonatal period. Thioredoxin system compensates for glutathione reductase deficiency. Significant transcriptomic differences occur from glutathione reductase deficiency. Lung structure and transcriptome normalizes by adulthood. More genes differentially expressed from glutathione reductase deficiency than oxygen.
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影响因子：
16.6
作者：
Eriksson, Sofi;Prigge, Justin R.;Talago, Emily A.;Arner, Elias S. J.;Schmidt, Edward E.
通讯作者：
Schmidt, Edward E.
影响因子：
7.4
作者：
Berkelhamer, Sara K.;Kim, Gina A.;Radder, Josiah E.;Wedgwood, Stephen;Czech, Lyubov;Steinhorn, Robin H.;Schumacker, Paul T.
通讯作者：
Schumacker, Paul T.
DOI：
10.1152/ajplung.00047.2016
发表时间：
2016-08-01
影响因子：
4.9
作者：
Lingappan, Krithika;Jiang, Weiwu;Moorthy, Bhagavatula
通讯作者：
Moorthy, Bhagavatula
影响因子：
3.4
作者：
LINDEMAN, JHN;LENTJES, EGWM;BERGER, HM
通讯作者：
BERGER, HM
影响因子：
5.1
作者：
Kotecha, S;Wangoo, A;Shaw, RJ
通讯作者：
Shaw, RJ