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: 7746428
• 负责人: Michael A O'Reilly
• 金额: $ 38.5万
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7746428
• 关键词: Adolescent; Adult; Affect; Alveolar; Asthma; Bacteria; Birth; Bronchopulmonary Dysplasia; Cell Culture Techniques; Cell Differentiation process; Child; Development; 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; public health relevance; repaired; respiratory; response; selective expression; stem cell division; surfactant; viral resistance

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.

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，早产儿仍经常需要氧气辅助，许多早产儿发生支气管肺发育不良（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。虽然许多接受氧气或患有BPD的婴儿最终离开医院，但即使在青少年时期，他们也经常表现出肺功能下降。此外，最近的流行病学研究表明，出生时暴露于高氧环境的儿童更容易感染病毒，哮喘，对二手烟的敏感性增加，并且比没有暴露于氧气的儿童更容易生病。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，我们确定了一种新的肺泡上皮II型细胞亚群，该细胞选择性地表达破坏RNA病毒和细菌的基因，并控制干/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型细胞对流感病毒和其他RNA病毒具有营养性。事实上，当小鼠感染甲型流感病毒时，II型细胞的这个亚群增殖，而其他II型细胞死亡。此外，成年小鼠暴露于高氧新生儿有简化的肺肺泡上皮II型细胞较少，I型细胞较多。当感染甲型流感病毒时，这些小鼠还表现出显著更大的炎症、纤维化和死亡率。基于这些研究结果，我们建议测试的假设，高氧永久性地破坏肺泡肺发育，刺激肺泡上皮II型分化为I型细胞，这是与增强流感病毒的易感性，由于损失的病毒耐药亚群的II型细胞。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早产儿一生中继续遭受呼吸道感染。公共卫生关系：早产儿暴露于高氧环境会破坏肺发育，并与肺功能的长期缺陷和呼吸道感染的易感性增加有关。通过定义高氧如何破坏新生小鼠肺泡上皮细胞分化，我们希望阐明它如何破坏肺发育以及为什么早产儿一生中继续遭受呼吸道感染。