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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

基本信息

批准号：
9172674
负责人：
Michael A O'Reilly
金额：
$ 11.51万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
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/9172674
关键词：
Affect Age Aging Air Alveolar Alveolar Cell Alveolus Animal Model Antibodies Birth CCL2 gene CD8B1 gene Cell surface Cells Child Development Diphtheria Disease Distal Elderly Environment Epithelial Exhibits Fibrosis Gene Expression Profile Genetic Goals Health Hospitalization Human Immune Immune response Individual Infection Inflammation Influenza A Virus, H1N1 Subtype Influenza A virus Injury Laboratories Lead Life Liquid substance Lung Lung diseases Maps Medical Morbidity - disease rate Mus Neonatal Hyperoxic Injury Oxygen Premature Infant Primary Infection Production Proteins Public Health Puerto Rico Reporter Research Research Support Ribonucleases Risk Severities Siblings Stem cells Structure of respiratory epithelium T-Lymphocyte Testing Toxin Type II Epithelial Receptor Cell Viral Viral Respiratory Tract Infection Virus Virus Diseases Work adaptive immunity aged base eosinophil human morbidity human mortality improved lung development lung injury molecular phenotype novel therapeutics oxidative damage parent grant pathogen postnatal respiratory response seasonal influenza senescence young adult

项目摘要

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.

项目总结（摘要）