Effect of Neonatal Hyperoxia on Alveolar Development and Infection

新生儿高氧对肺泡发育和感染的影响

• 批准号: 8197382
• 负责人: Michael A O'Reilly
• 金额: $ 38.12万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-10 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197382
• 关键词: Adolescent; Adult; Affect; Alveolar; Asthma; Bacteria; Birth; Bronchopulmonary Dysplasia; Cell Culture Techniques; Cell Differentiation process; Child; Development; EGF gene; Environmental air flow; Epidemiologic Studies; Epithelial; Epithelial Cells; Exhibits; Exposure to; Fibrosis; Future; Genes; Genomics; Hand; Hospitals; Human; Hyperoxia; Illness Days; Infant; Infection; Inflammation; Influenza; Influenza A virus; Left; Life; Lung; Mus; Neonatal; Newborn Infant; Oxidative Stress; Oxygen; Pathology; Predisposition; Premature Infant; Proliferating; Public Health; RNA Viruses; Reporter; Resistance; Respiratory Tract Infections; Respiratory physiology; Schools; Stem cells; Steroids; Superoxide Dismutase; Testing; Transgenic Mice; Type I Epithelial Receptor Cell; Type II Epithelial Receptor Cell; Virus; Virus Diseases; base; cell type; cigarette smoking; enhanced green fluorescent protein; extracellular; improved; influenzavirus; lung development; mortality; neonate; novel; premature; progenitor; repaired; respiratory; response; selective expression; stem cell division; surfactant; viral resistance

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.

抽象的 尽管使用了外源表面活性剂，类固醇和轻度通气，但早产儿通常需要 氧气辅助和许多人出现支气管肺发育不良（BPD）。 BPD是最常见的形式 新生儿中的慢性肺病，被认为是由破坏肺发育的氧化应激引起的。 当许多接受氧气或BPD遭受氧气或遭受BPD的婴儿最终离开医院，但他们经常表现出来 即使是青少年，肺功能也会降低。此外，最近的流行病学研究表明 出生时暴露于氧气升高的情况更可能患有病毒感染，哮喘，敏感性提高 二手香烟烟，比没有接触过的孩子更多 氧。因此，迫切需要了解氧化胁迫如何永久破坏肺 早产儿的发展以及这些变化如何增强对未来呼吸侮辱的敏感性。 在研究高氧如何破坏新生儿小鼠肺发育的同时，我们确定了一种新颖的 肺泡上皮II型细胞的亚群，这些细胞有选择地表达破坏RNA病毒和的基因 细菌和茎/祖细胞的不对称细胞分裂。这种推定的抗病毒 亚种群对于感染后肺泡修复可能至关重要，因为II型细胞是营养的 流感和其他RNA病毒。确实，这种II型细胞的亚群增殖而其他II型 当小鼠感染流感病毒时，细胞死亡。此外，暴露于高氧的成年小鼠 新生儿具有简化的肺，具有较少的肺泡上皮II型和更多的I型细胞。这些小鼠也是如此 当感染流感病毒时，表现出明显更大的炎症，纤维化和死亡率。基于 根据这些发现，我们建议检验高氧永久破坏肺泡的假设 通过刺激肺泡上皮II型对I型细胞的分化和 这与由于耐病毒的丧失而增强对流感病毒的敏感性有关 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 希望澄清它如何破坏新生儿肺发育以及为什么出生的婴儿过早受苦 一生中呼吸道感染。