Effect of Neonatal Hyperoxia on Alveolar Development and Infection

描述(申请人提供)：尽管使用了外源性表面活性物质、类固醇和温和的通风，但早产儿经常需要氧气辅助，许多人发展为支气管肺发育不良(BPD)。BPD是新生儿最常见的慢性肺部疾病，被认为是由破坏肺发育的氧化应激引起的。虽然许多接受氧气或患有BPD的婴儿最终出院，但他们经常表现出肺功能下降，即使在青少年时期也是如此。此外，最近的流行病学研究表明，与没有接触氧气的儿童相比，出生时暴露在高氧环境中的儿童更有可能患上病毒感染、哮喘、对二手烟烟雾的敏感性增加，以及更多的失学病假。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发育，以及这些变化如何增加对未来呼吸系统损害的易感性。在研究高氧如何破坏新生小鼠的肺发育时，我们发现了一种新的肺泡上皮II型细胞亚群，它选择性地表达摧毁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病毒具有营养作用。事实上，当小鼠感染甲型流感病毒时，这一亚群的II型细胞增殖，而其他II型细胞死亡。此外，成年小鼠在新生儿时期暴露于高氧环境中，肺组织变得简单，肺泡II型上皮细胞较少，而I型细胞较多。当感染甲型流感病毒时，这些小鼠也表现出显著更大的炎症、纤维化和死亡率。基于这些发现，我们建议检验这一假说，即高氧通过刺激肺泡II型上皮细胞向I型细胞分化而永久性地破坏肺泡发育，这与由于失去了II型细胞的抗病毒亚群而增加了对流感病毒的易感性有关。通过定义高氧如何影响肺泡上皮细胞分化，我们希望澄清它是如何破坏新生儿肺部发育的，以及为什么早产婴儿一生中都会继续患有呼吸道感染。公共卫生相关性：早产儿暴露在高氧环境中会扰乱肺部发育，并与肺功能长期受损和呼吸道感染易感性增加有关。通过定义高氧如何扰乱新生小鼠的肺泡上皮细胞分化，我们希望澄清它是如何扰乱肺发育的，以及为什么早产婴儿一生中都会继续患有呼吸道感染。

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.