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童年和成人疾病可以与环境联系起来 在重要的增长和发展阶段至关重要的阶段的暴露。过早出生是素 环境如何对以后的生活产生不利影响的示例。婴儿出生过早 不准备呼吸氧气的肺部欠发育。它们也可能暴露于多余的氧气中 用于减少组织缺氧的治疗方法，这可能导致支气管肺发育不良（BPD），A 在需要补充氧气的早产儿中发现的慢性肺疾病。虽然许多早产儿 最终离开医院，他们经常从各种持久的儿童和青少年遭受痛苦 肺部疾病（PPD），包括肺功能降低和呼吸道病毒感染增加。因此， 迫切需要了解出生时的氧气暴露如何永久破坏肺发育 早产儿以及这些持续性变化如何影响健康后期的健康。解决这个问题 需求，我们开发了一种新型模型，通过该模型将小鼠暴露于新生儿中，在房间中回收 空气，然后以成年人的流感病毒或博来霉素挑战。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降低的肺功能，轻度肺泡 简化与减少肺泡上皮II型细胞的数量相关，学习缺陷和年龄 相关的高血压。当感染流感病毒或施用的博来霉素时，成年小鼠暴露于 与暴露于的兄弟姐妹相比 房间空气为新生儿。同时研究早期氧气暴露的方式如何改变肺泡上皮 开发，我们发现出生时的氧气环境会影响II型细胞的扩展。相对于 在房间空气中观察到的内容，当小鼠分为低时，肺泡上皮II型细胞膨胀更高 （<17％）或高（E60％）氧。这意味着在低氧下最佳地发生II型细胞增殖 出生时暴露于房间的空气水平时，诸如胎儿的紧张局势会减少，并在高处再次增加 氧气张力。然后，当小鼠返回到小鼠时，增加了II型细胞数量的增加。 房间空气。因为II型细胞在先天免疫力中起重要作用，并且起到祖细胞的作用 上皮损伤后，它们的耗竭可能导致改变肺对肺泡的反应 上皮损伤。在这里，我们检验了以下假设，即出生控制的氧气环境适当 II型细胞的膨胀是保护成年肺免受肺泡上皮损伤所必需的。 了解出生控制下向氧气环境的过渡如何适当扩大肺泡 上皮II型细胞很重要，因为它可能会带来识别和治疗的新机会 过早出生的孩子有PPD风险。