Abstract
Lung and brain development is often altered in infants born preterm and exposed to excess oxygen, and this can lead to impaired lung function and neurocognitive abilities later in life. Oxygen-derived reactive oxygen species and the ensuing inflammatory response are believed to be an underlying cause of disease because over-expression of some anti-oxidant enzymes is protective in animal models. For example, neurodevelopment is preserved in mice that ubiquitously express human extracellular superoxide dismutase (EC-SOD) under control of an actin promoter. Similarly, oxygen-dependent changes in lung development are attenuated in transgenic SftpcEC−SOD mice that over-express EC-SOD in pulmonary alveolar epithelial type II cells. But whether anti-oxidants targeted to the lung provide protection to other organs, such as the brain is not known. Here, we use transgenic SftpcEC−SOD mice to investigate whether lung-specific expression of EC-SOD also preserves neurodevelopment following exposure to neonatal hyperoxia. Wild type and SftpcEC−SOD transgenic mice were exposed to room air or 100% oxygen between postnatal days 0–4. At 8 weeks of age, we investigated neurocognitive function as defined by novel object recognition, pathologic changes in hippocampal neurons, and microglial cell activation. Neonatal hyperoxia impaired novel object recognition memory in adult female but not male mice. Behavioral deficits were associated with microglial activation, CA1 neuron nuclear contraction, and fiber sprouting within the hilus of the dentate gyrus (DG). Over-expression of EC-SOD in the lung preserved novel object recognition and reduced the observed changes in neuronal nuclear size and myelin basic protein fiber density. It had no effect on the extent of microglial activation in the hippocampus. These findings demonstrate pulmonary expression of EC-SOD preserves short-term memory in adult female mice exposed to neonatal hyperoxia, thus suggesting anti-oxidants designed to alleviate oxygen-induced lung disease such as in preterm infants may also be neuroprotective.
Highlights
Supplemental oxygen used to treat preterm infants in respiratory distress has beneficial and harmful effects
Before testing whether over-expression of human extracellular superoxide dismutase (EC-SOD) in the lung preserves cognition in adult mice exposed to neonatal hyperoxia, we first confirmed human EC-SOD was expressed in the lung but not the brains of transgenic (Tg) mice
Lungs and brains were harvested from PND4 and 8 week-old wild type (WT) and SftpcEC−SOD transgenic (Tg) mice and immunoblotted with antibodies specific for the Tg human and endogenous mouse EC-SOD protein
Summary
Supplemental oxygen (hyperoxia) used to treat preterm infants in respiratory distress has beneficial and harmful effects. Preterm infants are sensitive to oxidative stress because maturation of anti-oxidant defenses in the lung does not occur until later in gestation and they have an impaired ability to stimulate expression of anti-oxidant molecules at birth [1]. They are systemically sensitive to oxidative stress. It is generally accepted that this enhanced sensitivity to oxygen and oxidative stress is responsible for why preterm infants are at increased risk for reduced lung function, being re-hospitalized following a respiratory viral infection, and developing airway wheezing later in life. Supplemental oxygen contributes significantly to respiratory morbidity in an oxygen-sensitive preterm infant
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