Neonatal Oxygen and Susceptibility to Respiratory Viral Infections

描述（由申请人提供）： 支气管肺发育不良（BPD）是一种慢性肺部疾病，见于早产儿，需要补充氧气和通气。虽然使用外源性表面活性剂和温和的通气策略降低了死亡率，但出院的婴儿即使在青少年时期也继续表现出肺功能下降。他们也更有可能患上哮喘，对二手烟敏感，感染呼吸道病毒后再次住院。由于这些发现表明BPD从未完全修复，因此迫切需要了解氧气补充如何永久性地破坏肺发育以及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并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，通常在2岁时在人类中遇到。与早产儿一样，新生儿暴露于高氧（高氧）的成年小鼠改变了肺顺应性，这归因于肺泡简化增加和上皮细胞分化破坏。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细胞反应，纤维化，并且与出生时暴露于室内空气的感染小鼠相比，死亡率增加。由于病毒清除也被延迟，我们假设，对发育中的肺进行高氧补充会通过破坏宿主有效清除呼吸道病毒的能力而增加感染的易感性。初步研究已经确定了三种可能的机制，呼吸道上皮发育的变化可能会影响对病毒感染的先天性和适应性免疫反应。在小鼠中研究这些机制的同时，将在接受高氧补充的早产儿中研究病毒清除和动员适当免疫反应的能力。通过整合小鼠和人类的研究结果，我们希望最终确定改善早产儿健康的新治疗机会。公共卫生相关性：早产儿暴露于高氧补充会破坏肺发育，并与肺功能的长期缺陷和呼吸道感染的易感性增加有关。通过整合从暴露于新生儿高氧的流感病毒感染成年小鼠中获得的研究结果与早产儿感染儿童的免疫反应，我们希望最终确定改善早产儿健康的新治疗机会。(End摘要）

DESCRIPTION (provided by applicant): 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 Avirus, 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. PUBLIC HEALTH RELEVANCE: Exposure of premature infants to high oxygen supplementation disrupts lung development, and is associated with long-term deficits in lung function and increased susceptibility to respiratory infections. By integrating research findings obtained from influenza virus infected adult mice exposed to neonatal hyperoxia with immune responses in infected children born prematurely, we hope to ultimately identify novel therapeutic opportunities for improving the health of children born prematurely. (End of Abstract)