Effect of Neonatal Hyperoxia on Alveolar Development and Infection

项目摘要(摘要) 季节性甲型流感病毒(IAV)导致相当大的人类发病率和死亡率 在世界各地。老年人出现呼吸道并发症和住院的风险最高， 幼儿，以及任何有某些潜在或既往健康状况的人，如出生 早产。由于早产儿经常暴露在高氧环境中，父母赠款使用小鼠进行研究 出生时异常的氧气环境如何改变肺部发育和宿主对甲型流感的反应 生命后期的病毒感染。我们的研究表明，年轻成年(8周大)小鼠暴露在100%的 出生前4天的氧气使肺泡简化，肺泡上皮II型(AECII)缺乏， 一种先天免疫的特异体和肺泡干细胞。他们还表现出更大的炎症和肺纤维化。 当感染IAV(HKx31，H3N1)时，感染的兄弟姐妹比出生在室内空气中的兄弟姐妹更容易患病。新生儿高氧血症 不会损害病毒特异性抗体的产生、CD8+T细胞的细胞溶解功能或 有效清除病毒。相反，使用白喉A毒素(DTA)的基因枯竭研究支持这样的观点 AECIIs的氧依赖缺失是导致远端肺泡细胞原发感染的原因， 从而增加上皮损伤、炎症和纤维化肺部疾病的严重程度。鉴于AECII 保护肺部免受感染，当肺部自然老化时，它们的丢失可能会导致 在感染IAV的动物模型和老年人类中看到的呼吸道发病率。因此，这次修订 补充检验了AECIIs在老年小鼠中的缺失将增强原发感染的假设 IAV类似于出生时暴露在高氧环境中的幼年成年小鼠。拟议的研究将 绘制小鼠增龄时AECIIs丢失的图谱，并确定增龄如何增强远端肺泡的原发感染 细胞，从而导致更大的上皮损伤、炎症和纤维性肺部疾病。了解如何 AECIIs的缺失影响小鼠宿主与病原体的相互作用，这一点很重要，因为它可能导致新的 降低易感人群肺部疾病严重程度的治疗方法。

PROJECT SUMMARY (ABSTRACT) Seasonal influenza A viruses (IAV) are responsible for considerable human morbidity and mortality throughout the world. The risk for respiratory complications and hospitalization is highest among the elderly, young children, and anyone with certain underlying or previous medical conditions, such as being born preterm. Since preterm infants are often exposed to high oxygen, the parent grant uses mice to investigate how an aberrant oxygen environment at birth alters lung development and the host response to influenza A virus infection later in life. Our research has shown how young adult (8 week old) mice exposed to 100% oxygen for the first 4 days of life have simplified alveoli that are deficient in alveolar epithelial type II (AECIIs), an innate immune privileged and alveolar stem cell. They also exhibit greater inflammation and fibrotic lung disease when infected with IAV (HKx31, H3N2) than infected siblings birthed into room air. Neonatal hyperoxia does not impair production of virus specific antibodies, cytolytic functions of CD8+T cells, or the ability to effectively clear virus. Instead, genetic depletion studies using diphtheria A toxin (DTA) support the idea that the oxygen-dependent loss of AECIIs is responsible for enhancing primary infection of distal alveolar cells, thereby increasing the severity of epithelial injury, inflammation, and fibrotic lung disease. Given that AECIIs protect the lung against infection, their loss as the lung naturally ages could contribute to the heightened respiratory morbidity seen in animal models and elderly humans infected with IAV. Hence, this Revision Supplement tests the hypothesis that the loss of AECIIs in aged mice will enhance primary infection to IAV similar to that of a young adult mouse exposed to high oxygen at birth. The proposed studies will map the loss of AECIIs as mice age and determine how aging enhances primary infection of distal alveolar cells, thereby resulting in greater epithelial injury, inflammation, and fibrotic lung disease. Understanding how the loss of AECIIs influences host-pathogen interactions in mice is important because it could lead to new therapies that reduce severity of lung diseases in susceptible individuals.