Aurothioglucose enhances proangiogenic pathway activation in lungs from room air and hyperoxia-exposed newborn mice

Abstract

Bronchopulmonary dysplasia (BPD), a long-term respiratory morbidity of prematurity, is characterized by attenuated alveolar and vascular development. Supplemental oxygen and immature antioxidant defenses contribute to BPD development. Our group identified thioredoxin reductase-1 (TXNRD1) as a therapeutic target to prevent BPD. The present studies evaluated the impact of the TXNRD1 inhibitor aurothioglucose (ATG) on pulmonary responses and gene expression in newborn C57BL/6 pups treated with saline or ATG (25 mg/kg ip) within 12 h of birth and exposed to room air (21% O2) or hyperoxia (>95% O2) for 72 h. Purified RNA from lung tissues was sequenced, and differential expression was evaluated. Hyperoxic exposure altered ~2,000 genes, including pathways involved in glutathione metabolism, intrinsic apoptosis signaling, and cell cycle regulation. The isolated effect of ATG treatment was limited primarily to genes that regulate angiogenesis and vascularization. In separate studies, pups were treated as described above and returned to room air until 14 days. Vascular density analyses were performed, and ANOVA indicated an independent effect of hyperoxia on vascular density and alveolar architecture at 14 days. Consistent with RNA-seq analyses, ATG significantly increased vascular density in room air, but not in hyperoxia-exposed pups. These findings provide insights into the mechanisms by which TXNRD1 inhibitors may enhance lung development.

Neonatal Selenium Deficiency Decreases Selenoproteins in the Lung and Impairs Pulmonary Alveolar Development

“…We observed no differences in the expression of several NRF-2 regulated genes or the protein contents of superoxide dismutases and catalase between neonatal Se sufficient and deficient lungs at P7. This is in contrast to prior reports demonstrating a compensatory increase in the NRF-2 associated genes Nqo1 , Gclc and Hmox1 , as well as other reports demonstrating an increase in non-Se containing AOE in lung or liver after dietary Se deficiency as well as genetic or pharmacologic Txnrd inhibition [ 35 , 40 , 41 , 42 , 53 , 54 , 70 , 71 , 72 , 73 , 74 ] There are several possible explanations why the neonatal SeD lung did not elicit a similar response despite decreased Txnrd activity. Differential pulmonary NRF-2 induction has been reported depending on the genetic strain of mouse evaluated, as well as the age and duration of insult [ 40 , 54 , 75 ].…”

“…The activity level of thioredoxin reductase was determined indirectly with an insulin disulfide reduction assay with NADPH and dithio-bis-(2-nitrobenzoic acid) (DTNB), as previously described and using manufacturer instructions (Cayman Chemicals, Ann Arbor, MI, USA) [ 40 , 41 , 42 ].…”

Ganduqing attenuates PM2.5-induced lung injury via regulating the pulmonary microbiota and metabolic profiles

“…Activation of this pathway can result in DNA damage and contribute to the development of lung tumors (Ma and Ma 2002). Additionally, the glutathione metabolism pathway has been identified as a significant biomarker of pulmonary endoplasmic reticulum (ER) stress and is crucial in the pathogenesis of lung injury (Dunigan-Russell et al 2020). The restoration of metabolic disorders observed in rats following GDQ intervention further supports the findings of metabolomics analysis, which partially elucidate the underlying mechanisms of lung injury induced by PM2.5 and highlight the protective effects of GDQ against PM2.5-induced lung injury.…”

The Role of the Thioredoxin System in Brain Diseases

“…Mammalian TrxRs are effectively inhibited by goldthioglucose (aurothioglucose, ATG) and other clinically used drugs [ 20 , 241 , 242 , 243 ]. ATG was the first TrxR inhibitor-containing gold [ 244 ]. Auranofin is a gold-containing complex used to treat rheumatoid arthritis, which inhibits the activity of TrxR, causing mitochondrial dysfunction, oxidative stress, and mitophagy flux to lysosomes [ 245 , 246 ].…”