Effect of Neonatal Hyperoxia on Alveolar Development and Infection

项目概要（摘要） 季节性甲型流感病毒（IAV）是造成人类发病率和死亡率的主要原因 在全世界都有。老年人呼吸系统并发症和住院的风险最高， 幼儿，以及任何有某些潜在或以前的医疗条件，如出生 早产儿由于早产儿经常暴露在高氧环境中， 出生时异常的氧环境如何改变肺部发育和宿主对甲型流感的反应 病毒感染后的生活我们的研究表明，年轻的成年（8周龄）小鼠暴露于100%的 出生后前4天的氧气简化了缺乏肺泡上皮II型（AECII）的肺泡， 先天免疫特权和肺泡干细胞。他们还表现出更大的炎症和纤维化肺 疾病时感染IAV（HKx 31，H3 N2）比感染同胞出生到室内空气。新生儿高氧 不损害病毒特异性抗体的产生、CD 8 +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）进行的基因耗竭研究支持以下观点： AECII的氧依赖性损失负责增强远端肺泡细胞的原发性感染， 从而增加上皮损伤、炎症和纤维化肺病的严重性。鉴于AECIIs 保护肺部免受感染，随着肺部自然老化，它们的损失可能会导致肺部感染的增加。 在感染IAV的动物模型和老年人中观察到的呼吸道发病率。因此，本次修订 补充剂检验了老年小鼠AECII缺失将增强原发性感染的假设， IAV类似于出生时暴露在高氧环境中的年轻成年小鼠。拟议的研究将 随着小鼠年龄的增长，绘制AECII的损失，并确定衰老如何增强远端肺泡的原发性感染， 细胞，从而导致更大的上皮损伤、炎症和纤维化肺病。了解如何 AECII的丧失影响小鼠中宿主-病原体相互作用是重要的，因为它可能导致新的 降低易感个体肺部疾病严重程度的疗法。

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.