S-Nitrosoglutathione Attenuates Airway Hyperresponsiveness in Murine Bronchopulmonary Dysplasia

Abstract

Bronchopulmonary dysplasia (BPD) is characterized by lifelong obstructive lung disease and profound, refractory bronchospasm. It is observed among survivors of premature birth who have been treated with prolonged supplemental oxygen. Therapeutic options are limited. Using a neonatal mouse model of BPD, we show that hyperoxia increases activity and expression of a mediator of endogenous bronchoconstriction, S-nitrosoglutathione (GSNO) reductase. MicroRNA-342-3p, predicted in silico and shown in this study in vitro to suppress expression of GSNO reductase, was decreased in hyperoxia-exposed pups. Both pretreatment with aerosolized GSNO and inhibition of GSNO reductase attenuated airway hyperresponsiveness in vivo among juvenile and adult mice exposed to neonatal hyperoxia. Our data suggest that neonatal hyperoxia exposure causes detrimental effects on airway hyperreactivity through microRNA-342-3p–mediated upregulation of GSNO reductase expression. Furthermore, our data demonstrate that this adverse effect can be overcome by supplementing its substrate, GSNO, or by inhibiting the enzyme itself. Rates of BPD have not improved over the past two decades; nor have new therapies been developed. GSNO-based therapies are a novel treatment of the respiratory problems that patients with BPD experience.

Tracheomalacia in bronchopulmonary dysplasia: Trachealis hyper‐relaxant responses to S‐nitrosoglutathione in a hyperoxic murine model

“…GSNOR expression and activity are increased in many subjects with asthma, and mice missing GSNOR are protected from experimental asthma . Our laboratory has shown that lung GSNOR activity and protein expression is markedly increased immediately following 3 weeks of neonatal murine hyperoxia exposure, in part, through posttranscriptional microRNA regulation . Immunohistochemical staining showed GSNOR localized to the proximal and distal BPD airway epithelium and smooth muscle .…”

“…Formation and bioactivity of these nitrogen oxide mediators, in turn, are tightly regulated in the smooth muscle microenvironment . Indeed, GSNOR and nitric oxide synthase (NOS) isoforms have been detected in the proximal and distal airways, primarily localizing to the airway epithelium . In the hyperoxic model, we have previously shown that endothelial NOS (eNOS) expression is increased in the BPD lung, notable because eNOS activation can induce counter‐regulatory GSNOR .…”

“…Newborn WT or GSNOR KO mice were pooled within 24 hours of birth into exposure groups. Litters, paired with a nursing dam, were placed in 60% oxygen (BPD) or room air (controls) for 21 days, as previously described …”

“…GSNO reductase (GSNOR), one of the primary enzymes responsible for GSNO catabolism, is elevated in the airways of patients with increased airway reactivity . While previous investigations of GSNOR and animal airway reactivity are in asthma, our research team has investigated airway hyperreactivity and bronchodilation in a neonatal sustained hyperoxia mouse model . We have found increased lung GSNOR activity and expression immediately following neonatal hyperoxia exposure compared to matched room air controls .…”

“…While previous investigations of GSNOR and animal airway reactivity are in asthma, our research team has investigated airway hyperreactivity and bronchodilation in a neonatal sustained hyperoxia mouse model . We have found increased lung GSNOR activity and expression immediately following neonatal hyperoxia exposure compared to matched room air controls . In vivo ventilator studies showed that aerosolized GSNO or an intraperitoneal injection of a GSNOR inhibitor (GSNORi) reversed hyperoxia‐induced hyperresponsiveness to methacholine (MCh) challenge in both juvenile and room air recovered adult mice.…”