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.

• Authors: Qian Li, Rui Li, Stephanie B Wall, Katelyn Dunigan, Changchun Ren, Tamas Jilling, Lynette K Rogers, Trent E Tipple
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 314 Issue 5 Pg. L736-L742 (05 01 2018) ISSN: 1522-1504 [Electronic] United States
• PMID: 29368550 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antirheumatic Agents
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Aurothioglucose
• NAD(P)H Dehydrogenase (Quinone)
• Nqo1 protein, mouse
• Thioredoxin Reductase 1
• Txnrd1 protein, mouse

Topics

• Animals
• Animals, Newborn
• Antirheumatic Agents (pharmacology)
• Aurothioglucose (pharmacology)
• Bronchopulmonary Dysplasia (drug therapy, metabolism, pathology)
• Cells, Cultured
• Female
• Gene Expression Regulation (drug effects)
• Lung (cytology, drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• NAD(P)H Dehydrogenase (Quinone) (genetics, metabolism)
• NF-E2-Related Factor 2 (genetics, metabolism)
• Pulmonary Alveoli (cytology, drug effects, metabolism)
• Thioredoxin Reductase 1 (genetics, metabolism)