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Aurothioglucose (ATG) and auranofin potently inhibit thioredoxin reductase-1 (TrxR1), and TrxR1 disruption activates nuclear factor E2\u2013related factor 2 (Nrf2), a regulator of endogenous antioxidant responses. We have shown previously that ATG safely and effectively prevents lung injury in adult murine models, likely via Nrf2-dependent mechanisms. The current studies tested the hypothesis that ATG would attenuate hyperoxia-induced lung developmental deficits in newborn mice. Newborn C3H\/HeN mice were treated with a single dose of ATG or saline within 12 hours of birth and were exposed to either room air or hyperoxia (85% O2). In hyperoxia, ATG potently inhibited TrxR1 activity in newborn murine lungs, attenuated decreases in body weight, increased the transcription of Nrf2-regulated genes nicotinamide adenine dinucleotide phosphate reduced quinone oxidoreductase-1 (NQO1) and heme oxygenase 1, and attenuated alterations in alveolar development. To determine the impact of TrxR1 inhibition on Nrf2 activation in vitro, murine alveolar epithelial-12 cells were treated with auranofin, which inhibited TrxR1 activity, enhanced Nrf2 nuclear levels, and increased NQO1 and heme oxygenase 1 transcription. Our novel data indicate that a single injection of the TrxR1 inhibitor ATG attenuates hyperoxia-induced alterations in alveolar development in newborn mice. Furthermore, our data support a model in which the effects of ATG treatment likely involve Nrf2 activation, which is consistent with our findings in other lung injury models. We conclude that TrxR1 represents a novel therapeutic target to prevent oxygen-mediated neonatal lung injury.<\/jats:p>","DOI":"10.1165\/rcmb.2015-0228oc","type":"journal-article","created":{"date-parts":[[2016,4,18]],"date-time":"2016-04-18T17:43:28Z","timestamp":1461001408000},"page":"419-428","source":"Crossref","is-referenced-by-count":50,"title":["Thioredoxin Reductase Inhibition Attenuates Neonatal Hyperoxic Lung Injury and Enhances Nuclear Factor E2\u2013Related Factor 2 Activation"],"prefix":"10.1093","volume":"55","author":[{"given":"Qian","family":"Li","sequence":"first","affiliation":[{"name":"Neonatal Redox Biology Laboratory"},{"name":"Division of Neonatology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie B.","family":"Wall","sequence":"additional","affiliation":[{"name":"Neonatal Redox Biology Laboratory"},{"name":"Division of Neonatology, 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