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Alterations of the Thioredoxin System by Hyperoxia

Implications for Alveolar Development

¹ Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital; ² Department of Pediatrics, Ohio State University College of Medicine, Columbus, Ohio; and ³ Division of Pulmonary Medicine, Department of Medicine, Emory University, Atlanta, Georgia

Correspondence and requests for reprints should be addressed to Trent E. Tipple, M.D., Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205. E-mail: trent.tipple{at}nationwidechildrens.org

Alterations in vascular endothelial growth factor (VEGF) contribute to alveolar simplification seen in animal models of bronchopulmonary dysplasia, and VEGF expression is redox regulated by thioredoxin (Trx)-1 in other diseases. The present studies tested the hypothesis that exposure to 85% O₂ negatively impacts the Trx1 system and VEGF expression in the lungs of newborn mice. There was no effect of fraction of inspired oxygen on lung Trx1 or Trx reductase-1 protein levels; however, lung Trx1 protein was predominantly oxidized in the lungs of newborn mice exposed to 85% O₂ by 24 hours of exposure. In room air (RA), lung Trx interacting protein (Txnip) levels decreased developmentally through Day 7 (1.0 ± 0.06 [Day 1] vs. 0.49 ± 0.10 [Day 3] vs. 0.29 ± 0.03 [Day 7]; P < 0.01), whereas VEGF expression increased (1.25 ± 0.16 [Day 1] vs. 4.35 ± 1.51 [Day 3] vs. 13.23 ± 0.37 [Day 7]; P < 0.01). Newborn mice exposed to 85% O₂ had no developmental decrease in Txnip protein levels and a delayed increase in VEGF protein levels. Lung Txnip and VEGF protein levels were different than in corresponding RA controls at Day 3, before the detection of lung morphologic abnormalities in our model. Txnip and VEGF protein levels were inversely correlated in both the RA and hyperoxia-exposed groups (n = 18; R = –0.66; P = 0.003). In conclusion, oxidation of Trx1 and sustained Txnip expression in the lungs of newborn mice exposed to 85% oxygen is likely to severely attenuate normal Trx1 function. The inverse correlation of Txnip with VEGF expression suggests that decreased Trx1 function contributes to the observed lung developmental abnormalities.

Key Words: hyperoxia • thioredoxin • thioredoxin interacting protein • vascular endothelial growth factor • bronchopulmonary dysplasia

CLINICAL RELEVANCE Premature birth into a hyperoxic environment relative to the in utero environment negatively impacts lung development and contributes to the development of bronchopulmonary dysplasia (BPD) in human infants. The present studies demonstrate that hyperoxia-induced alterations of the lung thioredoxin (Trx) system are inversely correlated with changes in vascular endothelial growth factor protein expression and precede observed alterations in alveolar development in a newborn mouse model of BPD. Similar effects of preterm birth on the Trx system in human infants could contribute to altered lung development that is characteristic of BPD.