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。 氧气补充和通风。虽然使用外源性表面活性物质和温和的通风 策略已经降低了死亡率，出院的婴儿甚至继续表现出肺功能下降 作为青少年。他们也更容易患哮喘，对二手烟烟雾敏感， 并在感染呼吸道病毒时再次住院。因为这些发现表明石油日产量永远不会完全 在修复过程中，迫切需要了解氧气补充是如何永久破坏肺的 以及这些变化如何增加对呼吸道侮辱的易感性。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扰乱肺发育和 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，2岁时经常在 人类。就像早产的孩子一样，暴露在高氧(高氧)下的成年小鼠就像新生儿一样 肺顺应性改变可归因于肺泡简化增加和上皮细胞破坏 差异化。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 与暴露在室内空气中的感染小鼠相比，反应、纤维化和死亡率增加 出生。因为病毒清除也被推迟了，我们假设高氧补充到 肺的发育会破坏宿主有效清除细菌的能力，从而增加对感染的易感性 呼吸道病毒。初步研究已经确定了三种可能的机制，通过这些机制， 呼吸道上皮发育可影响对病毒感染的先天和获得性免疫反应。而当 在小鼠身上研究这些机制，病毒清除和动员适当免疫的能力 将对接受高氧补充的早产儿的反应进行调查。通过 结合对老鼠和人类的研究结果，我们希望最终确定新的治疗机会 以改善早产儿童的健康。

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.