Alterations in vascular endothelial growth factor (VEGF) contribute to alveolar simplification seen in animal models of bronchopulmonary dysplasia (BPD) and VEGF expression is redox regulated by thioredoxin-1 (Trx1) 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 FiO2 on lung Trx1 or thioredoxin reductase-1 (TrxR1) protein levels, however lung Trx1 protein was predominantly oxidized in the lungs of newborn mice exposed to 85% O2 by 24 h of exposure. In room air, lung thioredoxin interacting protein (Txnip) levels decreased developmentally through day 7 (1.0±0.06 d1 vs 0.49±0.10 d3 vs 0.29±0.03 d7, p<0.01) while VEGF expression increased (1.25±0.16 d1 vs 4.35±1.51 d3 vs 13.23±0.37 d7, 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 corresponding room air controls at day 3, prior to the detection of lung morphologic abnormalities in our model. Txnip and VEGF protein levels were inversely correlated in both the room air 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.