Aurothioglucose does not improve alveolarization or elicit sustained Nrf2 activation in C57BL/6 models of bronchopulmonary dysplasia

Abstract

We previously showed that the thioredoxin reductase-1 (TrxR1) inhibitor aurothioglucose (ATG) improves alveolarization in hyperoxia-exposed newborn C3H/HeN mice. Our data supported a mechanism by which the protective effects of ATG are mediated via sustained nuclear factor E2-related factor 2 (Nrf2) activation in hyperoxia-exposed C3H/HeN mice 72 h after ATG administration. Given that inbred mouse strains have differential sensitivity and endogenous Nrf2 activation by hyperoxia, the present studies utilized two C57BL/6 exposure models to evaluate the effects of ATG on lung development and Nrf2 activation. The first model (0-14 days) was used in our C3H/HeN studies and the 2nd model (4-14 days) is well characterized in C57BL/6 mice. ATG significantly inhibited lung TrxR1 activity in both models; however, there was no effect on parameters of alveolarization in C57BL/6 mice. In sharp contrast to C3H/HeN mice, there was no effect of ATG on pulmonary NADPH quinone oxidoreductase-1 ( Nqo1) and heme oxygenase-1 ( Hmox1) at 72 h in either C57BL/6 model. In conclusion, although ATG inhibited TrxR1 activity in the lungs of newborn C57BL/6 mice, effects on lung development and sustained Nrf2-dependent pulmonary responses were blunted. These findings also highlight the importance of strain-dependent hyperoxic sensitivity in evaluation of potential novel therapies.

Mouse genetic background impacts susceptibility to hyperoxia‐driven perturbations to lung maturation

“…Inhibition of TXNRD with aurothioglucose attenuated the impact of hyperoxia on lung alveolarization, ostensibly through sustained activation of NFE2L2, which is a key regulator of antioxidant activity in the lung . Interestingly, and pertinent to this study, this effect was mouse strain dependent, where aurothioglucose was effective only in the C3H/HeN and not in the C57BL/6 strain . Data presented here indicate that the C57BL/6J has 5.2‐fold higher Txnrd1 baseline steady‐state mRNA levels than does the C3H/HeJ strain, and the C3H/HeJ strain has 155‐fold higher Txn1 baseline steady‐state mRNA levels than does the C57BL/6J strain.…”

“…For example, two studies on the impact of periostin on hyperoxia‐induced perturbations to lung alveolarization have revealed either no impact or a dramatic impact of periostin; where mouse strain was one of the several variables distinguishing the two studies. More recent studies have revealed that the mouse strain plays a key role in the evaluation of potentially useful pharmacological interventions in preclinical mouse models, where the utility of aurothioglucose to limit hyperoxia‐induced stunting of lung alveolarization was supported using the C3H/HeN mouse strain but not the C57BL/6J mouse strain . These studies highlight the importance of considering and accurately reporting the mouse strains used in experimental studies, and also, highlight a need for a side‐by‐side comparison of the impact of mouse strain on lung development in hyperoxia‐based BPD models.…”

“…Thioredoxin (Txn1) exerts antioxidant activity through facilitating reduction of other proteins by cysteine thiol‐disulfide exchange and has received much attention in preclinical BPD models, together with two TXNRD isozymes . Inhibition of TXNRD with aurothioglucose attenuated the impact of hyperoxia on lung alveolarization, ostensibly through sustained activation of NFE2L2, which is a key regulator of antioxidant activity in the lung .…”

“…The issue of inbred mouse strain in studies on lung development and BPD are also beginning to emerge, with one recent report highlighting that pharmacological intervention with the thioredoxin reductase‐1 inhibitor aurothioglucose prevented the deleterious effects of hyperoxia exposure on lung alveolarization in C3H/HeN mouse pups, but not in C57BL/6 mouse pups . These reports highlight that consideration of the mouse strain used in preclinical studies on BPD pathogenesis is essential for data interpretation, and for the comparison of experimental outcomes reported in different mouse strains in the literature.…”

Club Cell Heme Oxygenase-1 Deletion: Effects in Hyperoxia-Exposed Adult Mice

“…After equilibration, lungs were removed and fixed in buffered formalin overnight. Morphometric analyses for mean linear intercept (MLI) and radial alveolar count (RAC) were performed [29][30][31][32]. Assessments of H&E-stained lung sections were blindly performed by a pathologist, and indices of injury were scored using American Thoracic Society guidelines [33].…”