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

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.