Neonatal oxygen exposure alters airway hyper‐responsiveness but not the response to allergen challenge in adult mice

Abstract

Background Infants born prematurely are often treated with supplemental oxygen, which can increase their risk for airway hyperresponsiveness (AHR), asthma, reduced lung function, and altered responses to respiratory viral infections later in childhood. Likewise, exposure of newborn mice to hyperoxia alters baseline pulmonary mechanics and the host response to influenza A virus infection in adult mice. Here, we use this mouse model to test the hypothesis that neonatal hyperoxia also promotes AHR and exacerbated allergen-induced symptoms in adult mice. Methods Baseline lung mechanics and AHR measured by methacholine provocation were assessed in adult male and female mice exposed to room air or 100% oxygen (hyperoxia) between postnatal days 0 – 4. AHR and lung inflammation were evaluated after adult female mice were sensitized with ovalbumin (OVA) plus alum and challenged with aerosolized OVA. Results: Baseline lung compliance increased and resistance decreased in adult female, but not male, mice exposed to neonatal hyperoxia compared to siblings exposed to room air. Neonatal hyperoxia significantly enhanced methacholine-induced AHR in female mice, but did not affect allergen-induced AHR to methacholine or lung inflammation. Conclusion Increased incidence of AHR and asthma is reported in children born prematurely and exposed to supplemental oxygen. Our findings in adult female mice exposed to hyperoxia as neonates suggest that this AHR reported in children born prematurely may reflect non-atopic wheezing due to intrinsic structural changes in airway development.

Neonatal hyperoxia increases airway reactivity and inflammation in adult mice

“…In addition, there was a significant increase in AHR at baseline (pre‐methacholine) at 12 weeks in the hyperoxia group. The results are similar to increased AHR reported in adult female mice following neonatal hyperoxia . Our results imply that hyperoxic insult in the newborn may have long‐term pulmonary consequences, which could worsen, particularly with viral infections.…”

Pulmonary IL-1β expression in early life causes permanent changes in lung structure and function in adulthood

“…In the present study, female bitransgenic mice were more sensitive to increasing concentrations of MCh than male bitransgenic mice. Similar results have been found in mice exposed to neonatal hyperoxia (41) and in a mouse model of COPD (46,47). In the latter, ovariectomy or inhibition of estrogen receptor signaling attenuated airway remodeling and the increased distal airway resistance in female mice exposed to cigarette smoke (46,47).…”

Alternative Progenitor Lineages Regenerate the Adult Lung Depleted of Alveolar Epithelial Type 2 Cells

“…This time period of oxygen exposure represents the saccular phase of lung development in mice, which parallels the developmental stage when many preterm humans are born. At 8 weeks of age, mild airway hyperreactivity and alveolar simplification is seen in mice exposed to neonatal hyperoxia (8)(9)(10). Persistent inflammation and fibrotic lung disease is seen after these mice are infected with a sublethal dose of IAV (HKx31, H3N2) (11,12).…”