title: Thioredoxin Reductase Inhibition Attenuates Neonatal Hyperoxic Lung Injury and Enhances Nuclear Factor E2-Related Factor 2 Activation.
abstract: Oxygen toxicity and antioxidant deficiencies contribute to the development of bronchopulmonary dysplasia. Aurothioglucose (ATG) and auranofin potently inhibit thioredoxin reductase-1 (TrxR1), and TrxR1 disruption activates nuclear factor E2-related 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.
authors.affiliation: 1 Neonatal Redox Biology Laboratory.|2 Division of Neonatology, and.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: 1 Neonatal Redox Biology Laboratory.|2 Division of Neonatology, and.
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Wall
authors.affiliation: 2 Division of Neonatology, and.
authors.forename: Changchun
authors.initials: C
authors.lastname: Ren
authors.affiliation: 3 Department of Anesthesiology and Intensive Care Medicine, Rheinische Friedrich-Wilhelms University, University Medical Center, Bonn, Germany; and.
authors.forename: Markus
authors.initials: M
authors.lastname: Velten
authors.affiliation: 4 Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Hill
authors.affiliation: 5 Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Morgan L
authors.initials: ML
authors.lastname: Locy
authors.affiliation: 4 Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Lynette K
authors.initials: LK
authors.lastname: Rogers
authors.affiliation: 1 Neonatal Redox Biology Laboratory.|2 Division of Neonatology, and.
authors.forename: Trent E
authors.initials: TE
authors.lastname: Tipple
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001310:Auranofin / Q000494:pharmacology; D006051:Aurothioglucose / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D018496:Hyperoxia / Q000150:complications* / Q000201:enzymology* / Q000473:pathology; D055370:Lung Injury / Q000150:complications* / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D009024:Morphogenesis / Q000187:drug effects; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D006051:Aurothioglucose; D001310:Auranofin; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D013880:Thioredoxin-Disulfide Reductase
keywords: bronchopulmonary dysplasia; hyperoxia; nuclear factor E2–related factor 2; thioredoxin reductase