Sex-Associated Effects of Thioredoxin Reductase Inhibition in Hyperoxia-Induced Lung Injury in Adult Mice

Supraphysiological levels of oxygen are often used as therapy for acute respiratory distress and severe pulmonary morbidities but can cause excessive generation of reactive oxygen species resulting in oxidative and inflammatory injury. Aurothioglucose (ATG), an FDA-approved, gold-containing pharmaceutical, potently and irreversibly inhibits thioredoxin reductase 1, and ATG treatment preserves reduced glutathione levels and attenuates hyperoxic lung injury.

Adult C3H mice were treated with saline or ATG and exposed to room air (RA) or >95% O₂. All mice had succumbed or were euthanized at 200 h of >95% O₂. In a separate cohort euthanized at 72 h, prior to the appearance of oxygen toxicity, lung tissues were collected for metabolomic analyses. Comparisons were performed between RA and >95% O₂ exposure, saline and ATG treatment, and male and female.

In <95% O₂, differences in survival between the sexes with and without ATG treatment were observed. ATG-treated females survived longer than all other hyperoxia-exposed groups. Features in the glutathione and selenoprotein pathways were significantly different. Metabolomic analysis revealed keratan sulfate (KS) biosynthesis and glycosphingolipid (GSL) biosynthesis as the primary pathways affected in the saline O₂ vs. ATG O₂ comparison. Carnitine shuttle was identified as the primary pathway between the sexes both with ATG and O₂.

The current data suggest that the improved survival of hyperoxia-exposed, ATG-treated, female C3H mice may be driven by alterations in glutathione synthesis, energy production, and metabolism resulting in decreased lung injury. These findings may provide direction for further research to improve outcomes after hyperoxia exposure.