Effect of Neonatal Hyperoxia on Alveolar Development and Infection

摘要 尽管使用了外源性表面活性物质、类固醇和温和的呼吸机，早产儿经常需要 氧气辅助和许多人发展为支气管肺发育不良(BPD)。BPD是最常见的形式 新生儿的慢性肺部疾病，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 即使在青少年时期也会降低肺功能。此外，最近的流行病学研究表明，患有 出生时暴露在高氧环境中的人更有可能患有病毒感染、哮喘、敏感度增加 二手烟烟雾，以及比没有接触过二手烟的儿童更多的失学病假 氧气。因此，迫切需要了解氧化应激是如何永久性破坏肺部的。 早产儿的发育，以及这些变化如何增加对未来呼吸系统损害的易感性。 在研究高氧如何扰乱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病毒和 细菌，并控制干/祖细胞的不对称细胞分裂。这种假定的病毒具有抗药性 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。事实上，这一亚群的II型细胞在增殖，而其他II型细胞 当小鼠感染甲型流感病毒时，细胞死亡。此外，暴露在高氧中的成年小鼠 新生儿肺结构简化，肺泡II型上皮细胞较少，I型细胞较多。这些老鼠也 当感染甲型流感病毒时，表现出明显更严重的炎症、纤维化和死亡率。基座 根据这些发现，我们建议检验高氧永久性破坏肺泡的假设。 刺激肺泡II型上皮细胞分化为I型细胞的肺发育 这与流感病毒的易感性增加有关，因为失去了对病毒的抵抗力。 II型细胞亚群。通过定义高氧如何影响肺泡上皮细胞分化，我们 希望澄清它是如何扰乱新生儿肺发育的，以及为什么早产儿继续遭受痛苦 一生中不受呼吸道感染的影响。

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.