# Pharmacologic Inhibition of S-Nitrosoglutathione Reductase Prevents Hyperoxic Alveolar and Airway Disease in Newborn Mice

## TL;DR

This study shows that treating newborn mice with a drug that inhibits GSNO reductase prevents lung damage caused by high oxygen exposure, a condition similar to bronchopulmonary dysplasia in preterm infants.

## Contribution

The study demonstrates that early pharmacologic inhibition of GSNO reductase prevents hyperoxic lung disease in newborn mice.

## Key findings

- N6022 treatment improved alveolar simplification and airway tethering in a dose-dependent manner.
- N6022 reduced airway reactivity in hyperoxia-exposed pups, as shown by lower resistance and elastance.
- TGF-β expression was elevated in hyperoxia-exposed mice but reduced with N6022 treatment.

## Abstract

Background/Objectives: Preterm infants are at risk of developing the chronic lung condition of bronchopulmonary dysplasia (BPD), with associated alveolar simplification and airway hyperreactivity. Inhibition of S-nitrosoglutathione (GSNO) reductase has been shown to rescue airway hyperreactivity in a murine model of BPD. Here, we investigate the effects of early treatment with N6022, a pharmacologic GSNO reductase inhibitor. Methods: Newborn C57BL/6 mice were exposed to either 21% (control) or 60% oxygen (BPD model) for 5 days after birth. Pups simultaneously received either subcutaneous saline or varying doses of N6022 for 5 days during hyperoxia exposure. Pups were then recovered in room air to 3 weeks postnatal age. H&E-stained lungs were analyzed for alveolar simplification and airway tethering. In vivo airway reactivity to inhaled methacholine was measured using a flexiVent system. In separate littermates, lungs were immediately harvested after 5 days of hyperoxia for protein quantification via automated capillary Westerns. Results: Alveolar simplification and decreased airway tethering were noted in the 60% + saline group. Pups treated with N6022 during hyperoxia displayed dose-dependent improvements in alveolar simplification and airway tethering. Similarly, hyperoxia-exposed pups had increased airway reactivity, as measured by elevated respiratory system resistance and elastance responses to methacholine. Treatment with 10 mg/kg/day N6022 during hyperoxia resulted in decreased resistance and elastance responses. TGF-β expressions were elevated in the 60% + saline group and attenuated in the 60% + N6022 groups. Conclusions: Early exposure to GSNO reductase inhibitors such as N6022 can prevent hyperoxia-induced alveolar simplification and airway hyperreactivity, with lasting effects even after cessation of treatment.