Exogenous Hydrogen Sulfide Attenuates Hyperoxia Effects on Neonatal Mouse Airways

Supplemental O remains a necessary intervention for many premature infants (<34 wk gestation). Even moderate hyperoxia (<60% O) poses a risk for subsequent airway disease, thereby predisposing premature infants to pediatric asthma involving chronic inflammation, airway hyperresponsiveness (AHR), airway remodeling, and airflow obstruction. Moderate hyperoxia promotes AHR via effects on airway smooth muscle (ASM), a cell type that also contributes to impaired bronchodilation and remodeling (proliferation, altered extracellular matrix). Understanding mechanisms by which O initiates long-term airway changes in prematurity is critical for therapeutic advancements for wheezing disorders and asthma in babies and children. Immature or dysfunctional antioxidant systems in the underdeveloped lungs of premature infants thereby heightens susceptibility to oxidative stress from O. The novel gasotransmitter hydrogen sulfide (HS) is involved in antioxidant defense and has vasodilatory effects with oxidative stress. We previously showed that exogenous HS exhibits bronchodilatory effects in human developing airway in the context of hyperoxia exposure. Here, we proposed that exogenous HS would attenuate effects of O on airway contractility, thickness, and remodeling in mice exposed to hyperoxia during the neonatal period. Using functional [flexiVent; precision-cut lung slices (PCLS)] and structural (histology; immunofluorescence) analyses, we show that HS donors mitigate the effects of O on developing airway structure and function, with moderate O and HS effects on developing mouse airways showing a sex difference. Our study demonstrates the potential applicability of low-dose HS toward alleviating the detrimental effects of hyperoxia on the premature lung. Chronic airway disease is a short- and long-term consequence of premature birth. Understanding effects of O exposure during the perinatal period is key to identify targetable mechanisms that initiate and sustain adverse airway changes. Our findings show a beneficial effect of exogenous HS on developing mouse airway structure and function with notable sex differences. HS donors alleviate effects of O on airway hyperreactivity, contractility, airway smooth muscle thickness, and extracellular matrix deposition.