Effect of Neonatal Hyperoxia on Alveolar Development and Infection

描述（由申请人提供）：尽管使用外源性表面活性剂、类固醇和轻度通气，早产儿经常需要氧气辅助，许多早产儿发展为支气管肺发育不良（BPD）。BPD是新生儿中最常见的慢性肺部疾病，被认为是由破坏肺部发育的氧化应激引起的。虽然许多接受吸氧或患有BPD的婴儿最终离开了医院，但他们往往在青少年时期就表现出肺功能下降。此外，最近的流行病学研究表明，与没有接触过氧气的儿童相比，出生时暴露在高氧环境中的儿童更容易患病毒感染、哮喘、对二手烟的敏感度更高，以及更多的校外病假。因此，迫切需要了解氧化应激如何永久性地破坏早产儿的肺部发育，以及这些变化如何增加对未来呼吸道损伤的易感性。在研究高氧如何破坏新生小鼠的肺发育时，我们发现了一个新的肺泡上皮II型细胞亚群，它选择性地表达破坏RNA病毒和细菌的基因，并控制干细胞/祖细胞的不对称细胞分裂。这种假定的病毒抗性亚群可能对感染后的肺泡修复至关重要，因为II型细胞对流感和其他RNA病毒具有营养性。事实上，当小鼠感染甲型流感病毒时，这种II型细胞亚群增殖，而其他II型细胞死亡。此外，在新生儿时期暴露于高氧环境的成年小鼠肺结构简化，肺泡上皮II型细胞减少，I型细胞增多。这些小鼠在感染甲型流感病毒后也表现出明显更大的炎症、纤维化和死亡率。基于这些发现，我们建议验证高氧通过刺激肺泡上皮II型细胞向I型细胞的分化而永久性地破坏肺泡肺发育的假设，这与由于II型细胞抗病毒亚群的丧失而增强对流感病毒的易感性有关。通过定义高氧是如何影响肺泡上皮细胞分化的，我们希望阐明高氧是如何破坏新生儿肺部发育的，以及为什么早产婴儿在一生中会继续遭受呼吸道感染。公共卫生相关性：早产儿暴露于高氧环境会破坏肺部发育，并与肺功能长期缺陷和呼吸道感染易感性增加有关。通过定义高氧是如何破坏新生小鼠肺泡上皮细胞分化的，我们希望阐明高氧是如何破坏肺部发育的，以及为什么早产婴儿在一生中会继续遭受呼吸道感染。

DESCRIPTION (provided by applicant): Despite the use of exogenous surfactant, steroids, and mild ventilation, premature infants often require oxygen assistance and many develop bronchopulmonary dysplasia (BPD). BPD is the most common form of chronic lung disease in newborns and thought to be caused by oxidative stress that disrupts lung development. While many infants receiving oxygen or suffering from BPD eventually leave the hospital, they often exhibit reduced lung function even as adolescents. Moreover, recent epidemiologic studies indicate children who had been exposed to elevated oxygen at birth are more likely to have viral infections, asthma, increased sensitivity to second hand cigarette smoke, and more out-of-school sick days than children who were not exposed to oxygen. Thus, there is an urgent need to understand how oxidative stress permanently disrupts lung development in premature infants and how these changes enhance susceptibility to future respiratory insults. While investigating how hyperoxia disrupts lung development in neonatal mice, we identified a novel subpopulation of alveolar epithelial Type II cells that selectively expresses genes that destroy RNA viruses and bacteria, and control asymmetric cell division of stem/progenitor cells. This putative virus resistant subpopulation may be critical for alveolar repair following infection because Type II cells are trophic for influenza and other RNA viruses. Indeed, this subpopulation of Type II cells proliferated while other Type II cells died when mice were infected with influenza A virus. Moreover, adult mice exposed to hyperoxia as neonates have simplified lungs with fewer alveolar epithelial Type II and more Type I cells. These mice also exhibit significantly greater inflammation, fibrosis, and mortality when infected with influenza A virus. Based upon these findings, we propose to test the hypothesis that hyperoxia permanently disrupts alveolar lung development by stimulating the differentiation of alveolar epithelial Type II into Type I cells and this is associated with enhanced susceptibility to influenza virus due to loss of a virus-resistant subpopulation of Type II cells. By defining how hyperoxia affects alveolar epithelial cell differentiation, we hope to clarify how it disrupts neonatal lung development and why infants born prematurely continue to suffer from respiratory infections throughout life. PUBLIC HEALTH RELEVANCE: Exposure of premature infants to high oxygen disrupts lung development, and has been associated with long-term deficits in lung function and increased susceptibility to respiratory infections. By defining how high oxygen disrupts alveolar epithelial cell differentiation in neonatal mice, we hope to clarify how it disrupts lung development and why infants born prematurely continue to suffer from respiratory infections throughout life.