Effect of Neonatal Hyperoxia on Alveolar Development and Infection

摘要 尽管使用了外源性表面活性剂、类固醇和轻度通气，早产儿通常需要 氧气辅助和许多发展支气管肺发育不良（BPD）。BPD是最常见的 新生儿的慢性肺病，被认为是由氧化应激破坏肺发育引起的。 虽然许多接受氧气或患有BPD的婴儿最终离开医院，但他们经常表现出 即使在青少年时期，肺功能也会下降。此外，最近的流行病学研究表明， 出生时暴露在高氧环境中的人更容易感染病毒，哮喘，敏感性增加 二手烟，以及比没有接触二手烟的孩子更多的校外病假。 氧气因此，迫切需要了解氧化应激如何永久性地破坏肺 早产儿的发育以及这些变化如何增强对未来呼吸系统损伤的易感性。 在研究高氧如何破坏新生小鼠的肺发育时，我们发现了一种新的 肺泡上皮II型细胞亚群，选择性表达破坏RNA病毒的基因， 细菌，并控制干/祖细胞的不对称细胞分裂。这种假定的病毒抵抗 亚群对于感染后的肺泡修复可能是关键的，因为II型细胞是营养的， 流感病毒和其他RNA病毒。事实上，这种II型细胞亚群增殖，而其他II型细胞亚群增殖。 当小鼠感染甲型流感病毒时，细胞死亡。此外，成年小鼠暴露于高氧， 新生儿具有简化的肺，具有较少的肺泡上皮II型细胞和较多的I型细胞。这些小鼠还 当感染甲型流感病毒时，表现出显著更大的炎症、纤维化和死亡率。基于 基于这些发现，我们建议检验高氧永久性破坏肺泡 通过刺激肺泡上皮II型分化为I型细胞来促进肺发育， 这与对流感病毒的易感性增强有关， II型细胞的亚群。通过定义高氧如何影响肺泡上皮细胞分化，我们 我希望弄清楚它是如何破坏新生儿肺部发育的，以及为什么早产儿会继续受到影响 呼吸道感染的风险。

ABSTRACT 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.