Cumulative neonatal oxygen exposure predicts response of adult mice infected with influenza A virus.

An acceptable level of oxygen exposure in preterm infants that maximizes efficacy and minimizes harm has yet to be determined. Quantifying oxygen exposure as an area-under-the curve (OAUC ) has been predictive of later respiratory symptoms among former low birth weight infants. Here, we test the hypothesis that quantifying OAUC in newborn mice can predict their risk for altered lung development and respiratory viral infections as adults. Newborn mice were exposed to room air or a FiO2 of 100% oxygen for 4 days, 60% oxygen for 8 days, or 40% oxygen for 16 days (same cumulative dose of excess oxygen). At 8 weeks of age, mice were infected intranasally with a non-lethal dose of influenza A virus. Adult mice exposed to 100% oxygen for 4 days or 60% oxygen for 8 days exhibited alveolar simplification and altered elastin deposition compared to siblings birthed into room air, as well as increased inflammation and fibrotic lung disease following viral infection. These changes were not observed in mice exposed to 40% oxygen for 16 days. Our findings in mice support the concept that quantifying OAUC over a currently unspecified threshold can predict human risk for respiratory morbidity later in life. Pediatr Pulmonol. 2015; 50:222-230. © 2014 Wiley Periodicals, Inc.

Neonatal hyperoxia stimulates the expansion of alveolar epithelial type II cells.

Supplemental oxygen used to treat infants born prematurely disrupts angiogenesis and is a risk factor for persistent pulmonary disease later in life. Although it is unclear how neonatal oxygen affects development of the respiratory epithelium, alveolar simplification and depletion of type II cells has been observed in adult mice exposed to hyperoxia between postnatal Days 0 and 4. Because hyperoxia inhibits cell proliferation, we hypothesized that it depleted the adult lung of type II cells by inhibiting their proliferation at birth. Newborn mice were exposed to room air (RA) or hyperoxia, and the oxygen-exposed mice were recovered in RA. Hyperoxia stimulated mRNA expressed by type II (Sftpc, Abca3) and type I (T1α, Aquaporin 5) cells and inhibited Pecam expressed by endothelial cells. 5-Bromo-2'-deoxyuridine labeling and fate mapping with enhanced green fluorescence protein controlled statically by the Sftpc promoter or conditionally by the Scgb1a1 promoter revealed increased Sftpc and Abca3 mRNA seen on Day 4 reflected an increase in expansion of type II cells shortly after birth. When mice were returned to RA, this expanded population of type II cells was slowly depleted until few were detected by 8 weeks. These findings reveal that hyperoxia stimulates alveolar epithelial cell expansion when it disrupts angiogenesis. The loss of type II cells during recovery in RA may contribute to persistent pulmonary diseases such as those reported in children born preterm who were exposed to supplemental oxygen.

The role of hyperoxia in the pathogenesis of experimental BPD.

Supplemental oxygen is often used as a life-saving therapy in the treatment of preterm infants. However, its protracted use can lead to the development of bronchopulmonary dysplasia (BPD), and more recently, has been associated with adversely affecting the general health of children and adolescents who were born preterm. Efforts to understand how exposure to excess oxygen can disrupt lung development have historically focused on the interplay between oxidative stress and antioxidant defense mechanisms. However, there has been a growing appreciation for how changes in gene-environment interactions occurring during critically important periods of organ development can profoundly affect human health and disease later in life. Here, we review the concept that oxygen is an environmental stressor that may play an important role at birth to control normal lung development via its interactions with genes and cells. Understanding how changes in the oxygen environment have the potential to alter the developmental programing of the lung, such that it now proceeds along a different developmental trajectory, could lead to novel therapies in the prevention and treatment of respiratory diseases, such as BPD.

Neonatal oxygen increases sensitivity to influenza A virus infection in adult mice by suppressing epithelial expression of Ear1.

Oxygen exposure in premature infants is a major risk factor for bronchopulmonary dysplasia and can impair the host response to respiratory viral infections later in life. Similarly, adult mice exposed to hyperoxia as neonates display alveolar simplification associated with a reduced number of alveolar epithelial type II cells and exhibit persistent inflammation, fibrosis, and mortality when infected with influenza A virus. Because type II cells participate in innate immunity and alveolar repair, their loss may contribute to oxygen-mediated sensitivity to viral infection. A genomewide screening of type II cells identified eosinophil-associated RNase 1 (Ear1). Ear1 was also detected in airway epithelium and was reduced in lungs of mice exposed to neonatal hyperoxia. Electroporation-mediated gene delivery of Ear1 to the lung before infection successfully reduced viral replication and leukocyte recruitment during infection. It also diminished the enhanced morbidity and mortality attributed to neonatal hyperoxia. These findings demonstrate that novel epithelial expression of Ear1 functions to limit influenza A virus infection, and its loss contributes to oxygen-associated epithelial injury and fibrosis after infection. People born prematurely may have defects in epithelial innate immunity that increase their risk for respiratory viral infections.