Neonatal Redox Biology Laboratory, University of Alabama at Birmingham, Birmingham, AL, USA.
Division of Neonatology, University of Alabama at Birmingham, Birmingham, AL, USA.
Oxid Med Cell Longev. 2019 Jan 21;2019:7945983. doi: 10.1155/2019/7945983. eCollection 2019.
Aurothioglucose- (ATG-) mediated inhibition of thioredoxin reductase-1 (TXNRD1) improves alveolarization in experimental murine bronchopulmonary dysplasia (BPD). Glutathione (GSH) mediates susceptibility to neonatal and adult oxidative lung injury. We have previously shown that ATG attenuates hyperoxic lung injury and enhances glutathione- (GSH-) dependent antioxidant defenses in adult mice.
The present studies evaluated the effects of TXNRD1 inhibition on GSH-dependent antioxidant defenses in newborn mice and lung epithelia .
Newborn mice received intraperitoneal ATG or saline prior to room air or 85% hyperoxia exposure. Glutamate-cysteine ligase (GCL) catalytic (Gclc) and modifier (Gclm) mRNA levels, total GSH levels, total GSH peroxidase (GPx) activity, and Gpx2 expression were determined in lung homogenates. , murine transformed club cells (mtCCs) were treated with the TXNRD1 inhibitor auranofin (AFN) or vehicle in the presence or absence of the GCL inhibitor buthionine sulfoximine (BSO).
, ATG enhanced hyperoxia-induced increases in Gclc mRNA levels, total GSH contents, and GPx activity. , AFN increased Gclm mRNA levels, intracellular and extracellular GSH levels, and GPx activity. BSO prevented AFN-induced increases in GSH levels.
Our data are consistent with a model in which TXNRD1 inhibition augments hyperoxia-induced GSH-dependent antioxidant responses in neonatal mice. Discrepancies between and results highlight the need for methodologies that permit accurate assessments of the GSH system at the single-cell level.
硫代葡萄糖苷-（ATG-）介导的硫氧还蛋白还原酶-1（TXNRD1）抑制可改善实验性鼠支气管肺发育不良（BPD）中的肺泡化。谷胱甘肽（GSH）介导新生儿和成人氧化肺损伤的易感性。我们之前表明，ATG 可减轻高氧肺损伤并增强成年小鼠中依赖谷胱甘肽的抗氧化防御。
本研究评估了 TXNRD1 抑制对新生小鼠和肺上皮细胞中 GSH 依赖的抗氧化防御的影响。
新生小鼠在接受腹膜内 ATG 或生理盐水处理后，再暴露于室内空气或 85%高氧环境中。测定肺匀浆中的谷氨酸-半胱氨酸连接酶（GCL）催化（Gclc）和调节亚基（Gclm）mRNA 水平、总 GSH 水平、总 GSH 过氧化物酶（GPx）活性和 Gpx2 表达。在存在或不存在 GCL 抑制剂丁硫氨酸亚砜亚胺（BSO）的情况下，用 TXNRD1 抑制剂 auranoffin（AFN）或载体处理鼠转化的 club 细胞（mtCCs）。
在体内，ATG 增强了高氧诱导的 Gclc mRNA 水平、总 GSH 含量和 GPx 活性的增加。在体外，AFN 增加了 Gclm mRNA 水平、细胞内和细胞外 GSH 水平以及 GPx 活性。BSO 阻止了 AFN 诱导的 GSH 水平增加。
我们的数据与 TXNRD1 抑制增强新生小鼠高氧诱导的 GSH 依赖的抗氧化反应的模型一致。和之间的结果差异突出了需要采用能够在单细胞水平上准确评估 GSH 系统的方法学。
