BMAL1 sex-specific effects in the neonatal mouse airway exposed to moderate hyperoxia.

Supplemental O2 (hyperoxia) is a critical intervention for premature infants (<34 weeks) but consequently is associated with development of bronchial airway hyperreactivity (AHR) and asthma. Clinical practice shifted toward the use of moderate hyperoxia (<60% O2), but risk for subsequent airway disease remains. In mouse models of moderate hyperoxia, neonatal mice have increased AHR with effects on airway smooth muscle (ASM), a cell type involved in airway tone, bronchodilation, and remodeling. Understanding mechanisms by which moderate O2 during the perinatal period initiates sustained airway changes is critical to drive therapeutic advancements toward treating airway diseases. We propose that cellular clock factor BMAL1 is functionally important in developing mouse airways. In adult mice, cellular clocks target pathways highly relevant to asthma pathophysiology and Bmal1 deletion increases inflammatory response, worsens lung function, and impacts survival outcomes. Our understanding of BMAL1 in the developing lung is limited, but our previous findings show functional relevance of clocks in human fetal ASM exposed to O2. Here, we characterize Bmal1 in our established mouse neonatal hyperoxia model. Our data show that Bmal1 KO deleteriously impacts the developing lung in the context of O2 and these data highlight the importance of neonatal sex in understanding airway disease.

Exogenous hydrogen sulfide attenuates hyperoxia effects on neonatal mouse airways.

Supplemental O2 remains a necessary intervention for many premature infants (<34 wk gestation). Even moderate hyperoxia (<60% O2) 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 O2 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 O2. The novel gasotransmitter hydrogen sulfide (H2S) is involved in antioxidant defense and has vasodilatory effects with oxidative stress. We previously showed that exogenous H2S exhibits bronchodilatory effects in human developing airway in the context of hyperoxia exposure. Here, we proposed that exogenous H2S would attenuate effects of O2 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 H2S donors mitigate the effects of O2 on developing airway structure and function, with moderate O2 and H2S effects on developing mouse airways showing a sex difference. Our study demonstrates the potential applicability of low-dose H2S toward alleviating the detrimental effects of hyperoxia on the premature lung.NEW & NOTEWORTHY Chronic airway disease is a short- and long-term consequence of premature birth. Understanding effects of O2 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 H2S on developing mouse airway structure and function with notable sex differences. H2S donors alleviate effects of O2 on airway hyperreactivity, contractility, airway smooth muscle thickness, and extracellular matrix deposition.