| There is growing appreciation that environmental exposures during developmentally vulnerable periods of growth and maturation can influence the onset of many childhood and adult diseases. For example, individuals born preterm and exposed to excess levels of oxygen (hyperoxia) often exhibit reduced lung function, are frequently re-hospitalized following respiratory viral infections, and are at increased risk for neurodevelopmental impairment later in life. Similarly, adult mice exposed to hyperoxia during postnatal days (PND) 0-4 exhibit permanent changes in lung development, are more sensitive to influenza virus infection, and have an impaired ability to learn when compared to siblings birthed into room air. However, the dose of neonatal oxygen required to increase viral sensitivity remained unclear, and the pathways through which hyperoxia exerts these long-term changes are not completely understood. Therefore, the objectives of this thesis were to determine the dose of neonatal oxygen sufficient to disrupt the host response to viral infection in adult mice, and to investigate potential pathways through which early-life exposure to oxygen alters viral sensitivity and impairs neurodevelopment later in life. The results presented here demonstrate that exposure to more than 80% oxygen (FiO2) at birth (PND 0-4) is required to increase inflammation and promote fibrotic lung disease following infection in adult mice. Subsequent studies revealed that overexpression of the antioxidant extracellular superoxide dismutase (EC-SOD) in the respiratory epithelium prevents hyperoxia-induced fibrotic lung disease following infection, but not the excessive recruitment of leukocytes, which was attributed to monocyte chemoattractant protein (MCP)-1 gene expression. Lastly, it was determined that EC-SOD targeted to the lungs of mice protects against hyperoxia-mediated changes in the alveolar epithelium, and that this protection is associated with a preservation of the cognitive ability to learn. Taken together, these findings establish that lung development and the host response to influenza virus are altered by different doses of neonatal oxygen, and that neonatal hyperoxia alters the host response to influenza virus and impairs neurodevelopment through unique pathways. Ultimately, these studies support the use of neonatal hyperoxia as a model for continued investigation of long-term pulmonary and neurodevelopmental sequelae associated with preterm birth and early-life exposure to oxygen. |
