# S-Nitrosoglutathione therapy for oxidant disease of the neonatal airways and lung

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $592,303

## Abstract

Project Summary/Abstract:
In the United States, over 10,000 new diagnoses of the pediatric lung disease, bronchopulmonary dysplasia
(BPD), are made annually in surviving premature infants, with costs exceeding $2.5 billion. Treatment options,
such as adrenergic receptor agonists, have variable efficacy for the obstructive airway manifestations that
characterize this disease. Furthermore, these patients have an elevated risk of mortality and early onset chronic
obstructive pulmonary disease. In a neonatal hyperoxia mouse model of BPD and airway hyperreactivity, the
PI’s new data identify a viable therapy for this oxidant-related disease. Treatment with S-nitrosoglutathione
(GSNO) reverses airways hyperresponsiveness in oxygen exposed juvenile mice and room air recovered adults.
GSNO is a potent endogenous bronchodilator and anti-inflammatory, critical for the airways diseases of asthma
and cystic fibrosis. In this model, hyperoxia increases the catabolic breakdown of GSNO caused by increased
expression and activity of the enzyme, S-nitrosoglutathione reductase (GSNOR), in-part through hyperoxic
downregulation of a microRNA (miR-342). Furthermore, mice that do not express the GSNOR gene are protected
from hyperoxia induced alveolar simplification, airway hyperreactivity, and end-organ pulmonary hypertensive
changes. This proposal will test the overall hypotheses that (1) molecular GSNOR catabolism of beneficial GSNO
in relevant cells drives the development of BPD and (2) genetic or pharmacologic targeting of the GSNO/GSNOR
pathway will mitigate inflammation and disease. This proposal will evaluate the effects of neonatal hyperoxia in
genetic GSNOR knock-outs by investigating the molecular mechanisms in which GSNO confers protection,
distinguish gene expression profiles at a single-nucleus level in lung tissue from wild type and GSNOR knock-
outs, elucidate the roles of GSNOR in alveolar & airway epithelial cells or myeloid immune cells using Cre/loxP
cell-specific knock-outs, and test pharmacologic GSNOR inhibition or exogenous inhaled GSNO during
hyperoxia. These studies are clinically important because inhaled GSNO and GSNOR inhibitors are being
studied for airway diseases such as asthma and cystic fibrosis which could ultimately serve as viable new
therapies for BPD.

## Key facts

- **NIH application ID:** 10855097
- **Project number:** 1R01HL172894-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Thomas Michael Raffay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $592,303
- **Award type:** 1
- **Project period:** 2024-04-15 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10855097

## Citation

> US National Institutes of Health, RePORTER application 10855097, S-Nitrosoglutathione therapy for oxidant disease of the neonatal airways and lung (1R01HL172894-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10855097. Licensed CC0.

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