Effect of Neonatal Hyperoxia on Alveolar Development and Infection

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发育关键阶段的环境暴露有关。早产是环境如何对生命后期健康产生不利影响的一个主要例子。早产儿肺部发育不全，无法呼吸氧气。他们也可能暴露在用于治疗减少组织缺氧的过量氧气中，这可能导致支气管肺发育不良（BPD），这是一种慢性肺部疾病，常见于需要补充氧气的早产儿。虽然许多早产儿最终离开了医院，但他们在儿童和青少年时期往往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以后的健康和福祉。为了满足这一需求，我们开发了一种新的模型，通过该模型，小鼠在新生儿时期暴露于高氧环境中，在室内空气中恢复，然后在成年后接受甲型流感病毒或博来霉素的挑战。与早产儿童类似，暴露于新生儿高氧的成年小鼠表现出肺功能降低，肺泡轻度简化，肺泡上皮II型细胞数量减少，学习障碍和年龄相关性高血压。当感染甲型流感病毒或

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.