Neonatal Oxygen and Susceptibility to Respiratory Viral Infections

摘要 支气管肺发育不良（BPD）是一种慢性肺部疾病，见于早产儿， 氧气补充和通气。虽然使用外源性表面活性剂和轻度通气 尽管这些策略降低了死亡率，但出院的婴儿仍然表现出肺功能下降， 作为青少年。他们也更容易患哮喘，对二手烟敏感， 并在感染呼吸道病毒时再次住院。由于这些发现表明BPD从未完全 因此，迫切需要了解氧气补充如何永久性地破坏肺部 这些变化如何增强对呼吸系统损伤的易感性。为了满足这一需求，我们 开发了一种小鼠模型，以了解短期氧气暴露如何破坏肺部发育， 改变对甲型流感病毒感染的反应，甲型流感病毒是一种常见的呼吸道病毒， 人类像早产的孩子一样，成年小鼠在新生儿时暴露在高氧环境中， 改变肺顺应性，归因于肺泡简化增加和上皮细胞破坏 分化当感染甲型流感病毒时，这些小鼠表现出持续的炎症，改变了T细胞， 与暴露于室内空气的感染小鼠相比， 出生由于病毒清除也被延迟，我们假设，高氧补充， 发育中的肺通过破坏宿主有效清除 呼吸道病毒初步研究确定了三种可能的机制， 呼吸道上皮的发育可能影响对病毒感染的先天性和适应性免疫应答。而 在小鼠中研究这些机制，病毒清除和动员适当免疫的能力， 将在接受高氧补充的早产儿中研究反应。通过 结合小鼠和人类的研究结果，我们希望最终确定新的治疗机会， 来改善早产儿的健康。

ABSTRACT Bronchopulmonary dysplasia (BPD) is a chronic lung disease seen in premature infants requiring oxygen supplementation and ventilation. Although the use of exogenous surfactant and mild ventilation strategies has reduced mortality, infants who leave the hospital continue to exhibit reduced lung function even as adolescents. They are also more likely to develop asthma, be sensitive to second hand cigarette smoke, and be re-hospitalized when infected with respiratory viruses. Since these findings suggest BPD never fully repairs, there is an urgent need to understand how oxygen supplementation permanently disrupts lung development and how these changes enhance susceptibility to respiratory insults. To address this need, we developed a mouse model to understand how short-term oxygen exposure disrupts lung development and alters the response to influenza A virus infection, a common respiratory virus often encountered by age 2 in humans. Like children born prematurely, adult mice exposed to high oxygen (hyperoxia) as newborns had altered lung compliance that was attributed to increased alveolar simplification and disrupted epithelial cell differentiation. When infected with influenza A virus, these mice showed persistent inflammation, altered T cell responses, fibrosis, and increased mortality compared to infected mice that had been exposed to room air at birth. Because viral clearance was also delayed, we hypothesize that high oxygen supplementation to the developing lung increases susceptibility to infection by disrupting the host's ability to effectively clear respiratory viruses. Preliminary studies have identified three possible mechanisms by which changes in respiratory epithelial development could affect innate and adaptive immune responses to viral infection. While investigating these mechanisms in mice, viral clearance and ability to mobilize an appropriate immune response will be investigated in children born prematurely that received high oxygen supplementation. By integrating research findings in mice and humans, we hope to ultimately identify novel therapeutic opportunities for improving the health of children born prematurely.