Buczynski Bradley W, Mai Nguyen, Yee Min, Allen Joshua L, Prifti Landa, Cory-Slechta Deborah A, Halterman Marc W, O'Reilly Michael A
Department of Environmental Medicine, University of Rochester, Rochester, NY, United States.
Department of Neurology, University of Rochester, Rochester, NY, United States.
Front Med (Lausanne). 2018 Dec 10;5:334. doi: 10.3389/fmed.2018.00334. eCollection 2018.
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 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 mice to investigate whether lung-specific expression of EC-SOD also preserves neurodevelopment following exposure to neonatal hyperoxia. Wild type and 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.
早产且暴露于过量氧气的婴儿，其肺部和大脑发育常常会发生改变，这可能导致日后生活中肺功能和神经认知能力受损。氧衍生的活性氧物种以及随之而来的炎症反应被认为是疾病的一个潜在原因，因为在动物模型中一些抗氧化酶的过度表达具有保护作用。例如，在肌动蛋白启动子控制下普遍表达人细胞外超氧化物歧化酶（EC-SOD）的小鼠，其神经发育得以保留。同样，在肺泡II型上皮细胞中过度表达EC-SOD的转基因小鼠，其肺部发育中依赖氧气的变化会减弱。但针对肺部的抗氧化剂是否能对其他器官（如大脑）提供保护尚不清楚。在此，我们使用转基因小鼠来研究EC-SOD的肺特异性表达在暴露于新生儿高氧环境后是否也能保留神经发育。野生型和转基因小鼠在出生后第0 - 4天暴露于室内空气或100%氧气中。在8周龄时，我们通过新物体识别、海马神经元的病理变化和小胶质细胞活化来研究神经认知功能。新生儿高氧环境损害了成年雌性而非雄性小鼠的新物体识别记忆。行为缺陷与小胶质细胞活化、CA1神经元核收缩以及齿状回（DG）门区内的纤维芽生有关。肺中EC-SOD的过度表达保留了新物体识别能力，并减少了观察到的神经元核大小和髓鞘碱性蛋白纤维密度的变化。它对海马中小胶质细胞活化的程度没有影响。这些发现表明，EC-SOD的肺部表达保留了暴露于新生儿高氧环境的成年雌性小鼠的短期记忆，因此表明旨在减轻氧诱导的肺部疾病（如早产儿）的抗氧化剂也可能具有神经保护作用。
