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: 9000732
• 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/9000732
• 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; Infection; Inflammation; Influenza A virus; Injury; Lead; Learning; Left; Life; Link; Lung; Lung diseases; Modeling; Mus; Natural Immunity; Neonatal Hyperoxic Injury; Newborn Infant; Oxidation-Reduction; Oxygen; Play; Population; Premature Infant; 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; Viral Respiratory Tract Infection; Virus Diseases; age related; alveolar epithelium; base; birth control; eosinophil; extracellular; injured; insight; lung development; neonate; novel; overexpression; postnatal; protein function; repaired; response

DESCRIPTION (provided by applicant): 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 (¿60%) 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.

描述（由申请人提供）：越来越多的证据表明，许多儿童和成人疾病可能与生长和发育的关键重要阶段的环境暴露有关。 早产是环境如何对以后的生活产生不利影响的一个主要例子。早产儿的肺部发育不全，无法呼吸氧气。他们也可能暴露于过量的氧气，用于治疗以减少组织缺氧，这可能导致支气管肺发育不良（BPD），这是一种在需要补充氧气的早产儿中发现的慢性肺部疾病。虽然许多早产儿最终离开医院，但他们通常在儿童和青少年时期患有各种持续性肺部疾病（PPD），包括肺功能下降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性地破坏早产儿的肺部发育，以及这些持续的变化如何影响生命后期的健康和福祉。为了满足这一需求，我们开发了一种新的模型，通过该模型，小鼠在新生儿时暴露于高氧，在室内空气中恢复，然后在成年时用甲型流感病毒或博来霉素进行攻击。与早产儿类似，暴露于新生儿高氧的成年小鼠表现出肺功能降低、与肺泡上皮II型细胞数量减少相关的轻度肺泡简化、学习缺陷和年龄相关的高血压。当感染甲型流感病毒或 在施用博来霉素后，与在新生时暴露于室内空气的同胞相比，暴露于新生高氧的成年小鼠显示出增加的炎症和纤维化疾病。在研究早期氧暴露如何改变肺泡上皮发育的过程中，我们发现出生时的氧环境会影响II型细胞的扩张。相对于在室内空气中观察到的情况，当小鼠在低氧（<17%）或高氧（<$60%）下出生时，肺泡上皮II型细胞扩增更高。 这意味着II型细胞增殖在低氧张力下最佳地发生，例如在胎儿中，当出生时暴露于室内空气水平时减少，并且在高氧张力下再次增加。当小鼠回到室内空气中时，这种增加的II型细胞数量被过度修剪。由于II型细胞在先天免疫中发挥重要作用，并在上皮损伤后作为祖细胞发挥作用，因此它们的耗竭可能是改变肺对肺泡上皮损伤的反应方式的原因。在这里，我们测试的假设，出生时的氧气环境控制适当的扩展II型细胞，这是必要的，以保护成人肺肺泡上皮细胞损伤。了解在出生时过渡到氧气环境如何控制肺泡上皮II型细胞的适当扩张是重要的，因为它可能会为识别和治疗有PPD风险的早产儿带来新的机会。