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.

Role of the Nrf2/HO-1 axis in bronchopulmonary dysplasia and hyperoxic lung injuries

“…Nrf2 activation in turn is able to overexpress, in these models, downstream expression of NQO1. Recently, the same research group obtained similar results in a model of newborn mice exposed to hyperoxia [71]. Indeed, they observed enhanced Nrf2 levels upon TrxR1 inhibition by a single dose of ATG.…”

“…Indeed, they observed enhanced Nrf2 levels upon TrxR1 inhibition by a single dose of ATG. Moreover, inhibition of TrxR1 in murine alveolar epithelial-12 cells by auranofin leads to Nrf2 overexpression with a consequent enhanced transcription of NQO1 and HO-1 [71].…”

Antioxidative effects of caffeine in a hyperoxia-based rat model of bronchopulmonary dysplasia

“…In addition, there was a significant induction of HO-1 at P3. Li et al demonstrated an induction of HO-1 after hyperoxic exposure for 3 days in newborn mice [55].…”

Attenuated SUMOylation of sirtuin 1 in premature neonates with bronchopulmonary dysplasia

“…Supplemental oxygen is an important aspect of treatment of premature neonates with respiratory failure. However, hyperoxic exposure triggers oxidative stress, results in lung injury and contributes to the development of BPD (3,4). Infants with BPD who were administered higher concentrations of supplemental oxygen were previously demonstrated to have more persistent lung disease (4).…”

“…Supplemental oxygen is an important aspect of treatment of respiratory failure in premature neonates. However, oxidative stress induced by hyperoxic exposure results in overproduction of reactive oxygen metabolites (including hydrogen peroxide, singlet oxygen, superoxide free radicals, and hydroxyl free radicals), which overwhelms the immature antioxidant enzyme systems of premature neonates, causes lung injury, impairs alveolarization and leads to BPD (3,4).…”