Sex-Dependent Effects of Thioredoxin Reductase Inhibition in Acute Lung Injury in Adult Mice

Supraphysiological levels of oxygen are often used as therapy for acute respiratory distress and other severe pulmonary morbidities but can cause excessive generation of reactive O₂ and nitrogen species resulting in oxidative and inflammatory injury. Aurothioglucose (ATG), a FDA approved, gold-containing pharmaceutical, potently and irreversibly inhibits TrxR1 and in adult and neonatal mice, 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 or >95% O₂. All mice had succumbed or were euthanized at 200h of hyperoxia exposure and lung tissues were collected. Metabolomic analyses were conducted and comparisons were performed between room air and >95% O₂ exposure, saline and ATG treatment, and male and female sex. Profound differences in survival between sexes with and without ATG treatment with ATG-treated females surviving longer than all other hyperoxia-exposed groups. Comparisons between groups identified metabolites in the glutathione pathway as significantly different. Metabolomic analysis revealed keratin sulfate (KS) biosynthesis and glycosphingolipid (GSL) biosynthesis as the primary pathways in the saline O₂ vs ATG O₂ comparison. Carnitine shuttle was identified as the primary pathway between sexes both with ATG and O₂. The current data suggests that the improved survival of hyperoxia-exposed ATG-treated female C3H mice is likely driven by enhanced glutathione synthesis, energy production, and metabolism resulting in decreased lung injury through modulation of KS and GSL levels. These findings may provide direction for further research to improve outcomes after hyperoxia exposure.