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: 8630581
• 负责人: Michael A O'Reilly
• 金额: $ 38.38万
• 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 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630581
• 关键词: Address; Adolescent; Adult; Affect; Air; Alveolar; Birth; Bleomycin; Bronchopulmonary Dysplasia; Cartoons; Cell Proliferation; Cells; Child; Childhood; Chronic lung disease; Development; Disease; Environment; Environmental Exposure; Epithelial; Epithelial Cells; Exhibits; Fetal Lung; Fetus; Fibrosis; Funding; Goals; Growth and Development function; Health; Hospitals; Hyperoxia; Hypertension; Hypoxia; Immune; Immune response; Infant; Infection; Inflammation; Influenza A virus; Injury; Lead; Learning; Left; Life; Link; Lung; Lung diseases; Modeling; Mus; Natural Immunity; Neonatal; Newborn Infant; Oxidation-Reduction; Oxygen; Oxygen measurement, partial pressure, arterial; Play; Population; Premature Infant; Relative (related person); Reporter; Respiratory physiology; Ribonucleases; Risk; Role; Siblings; Staging; Stem cells; Superoxide Dismutase; Testing; Tissues; Transgenic Mice; Type I Epithelial Receptor Cell; Type II Epithelial Receptor Cell; Viral; Virus Diseases; age related; alveolar epithelium; base; birth control; eosinophil; extracellular; injured; insight; lung development; neonate; novel; postnatal; protein function; public health relevance; repaired; respiratory; response

There is growing evidence that many childhood and adult diseases can be linked to environmental exposures during critically important stages of growth and development. Being born prematurely is a prime example of how the environment can adversely affect health later in life. Infants born prematurely have underdeveloped lungs that are not prepared to breath oxygen. They may also be exposed to excess oxygen used therapeutically to reduce tissue hypoxia and this can lead to bronchopulmonary dysplasia (BPD), a chronic lung disease seen in preterm infants needing supplemental oxygen. While many preterm infants eventually leave the hospital, they often suffer as children and adolescents from a variety of persistent pulmonary diseases (PPD), including reduced lung function and increased respiratory viral infections. Thus, there is an urgent need to understand how oxygen exposure at birth permanently disrupts lung development in preterm infants and how these persistent changes affect health and wellbeing later in life. To address this need, we developed a novel model by which mice are exposed to hyperoxia as neonates, recovered in room air, and then challenged with influenza A virus or bleomycin as adults. Analogous to children born prematurely, adult mice exposed to neonatal hyperoxia exhibit reduced lung function, mild alveolar simplification associated with reduced numbers of alveolar epithelial type II cells, learning deficits, and age- related hypertension. When infected with influenza A virus or administered bleomycin, adult mice exposed to neonatal hyperoxia displayed increased inflammation and fibrotic disease compared to siblings exposed to room air as neonates. While investigating how early-life oxygen exposure alters alveolar epithelial development, we discovered the oxygen environment at birth affects the expansion of type II cells. Relative to what is observed in room air, alveolar epithelial type II cell expansion is higher when mice are birthed into low (<17%) or high (e60%) oxygen. This implies type II cell proliferation occurs optimally under low oxygen tensions, such as in the fetus, is reduced when exposed to room air levels at birth, and increases again at high oxygen tensions. This increased number of type II cells is then excessively pruned when mice are returned to room air. Because type II cells play an important role in innate immunity and function as progenitor cells following epithelial injury, their depletion could be responsible for altering how the lung responds to alveolar epithelial injury. Here, we test the hypothesis that the oxygen environment at birth controls proper expansion of type II cells, which are necessary to protect the adult lung from alveolar epithelial injury. Understanding how the transition to the oxygen environment at birth controls proper expansion of alveolar epithelial type II cells is important because it could lead to new opportunities for identifying and treating children born prematurely who are at risk for PPD.

越来越多的证据表明，许多儿童和成人疾病都与环境有关。 在生长和发育的关键阶段暴露。早产是一个质数 环境如何对以后的生活产生不利影响的例子。早产儿有 发育不全的肺无法呼吸氧气他们也可能暴露在过量的氧气中 治疗上用于减少组织缺氧，这可能导致支气管肺发育不良（BPD）， 需要补充氧气的早产儿的慢性肺病。虽然许多早产儿 最终离开医院，他们往往遭受作为儿童和青少年从各种持久的 肺部疾病（PPD），包括肺功能下降和呼吸道病毒感染增加。因此，在本发明中， 迫切需要了解出生时的氧气暴露如何永久性地破坏肺发育， 早产儿以及这些持续的变化如何影响生命后期的健康和福祉。为了解决这个 需要，我们开发了一种新的模型，通过该模型，小鼠在新生时暴露于高氧，在室内恢复， 空气中，然后用甲型流感病毒或博来霉素作为成虫进行攻击。类似于出生的孩子 过早暴露于新生儿高氧的成年小鼠表现出肺功能降低，轻度肺泡炎， 与肺泡上皮II型细胞数量减少、学习缺陷和年龄相关的简化- 高血压相关当感染甲型流感病毒或给予博莱霉素时，暴露于 新生儿高氧显示增加炎症和纤维化疾病相比，兄弟姐妹暴露于 空气清新如新生儿。在研究生命早期的氧气暴露如何改变肺泡上皮细胞时， 我们发现出生时的氧气环境会影响II型细胞的扩张。相对于 在室内空气中观察到的，肺泡上皮II型细胞的扩张较高，当小鼠出生在低 （<17%）或高（e60%）氧。这意味着II型细胞增殖最佳发生在低氧下 紧张，如在胎儿中，在出生时暴露于室内空气水平时减少，并在高空气水平时再次增加。 氧张力这种增加的II型细胞的数量，然后过度修剪时，小鼠返回 室内空气由于II型细胞在先天免疫中起着重要作用，并作为祖细胞发挥功能 在上皮损伤后，它们的消耗可能是改变肺对肺泡上皮细胞的反应的原因。 上皮损伤在这里，我们测试的假设，氧气环境在出生控制适当 II型细胞的扩增，这是保护成人肺免受肺泡上皮损伤所必需的。 了解出生时向氧气环境的过渡如何控制肺泡的适当扩张 上皮II型细胞是重要的，因为它可能导致新的机会，识别和治疗 早产儿有患PPD的风险。