COLLECTINS AND LUNG DEFENSE

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The present application seeks to determine the effect of viral infection on surfactant homeostasis and the role of surfactant protein-A (SP-A) in protecting the lung from viral infection. The lung is continually exposed to inhaled pathogens, yet, remains remarkably free from infection. SP-A is an abundant lung selective collectin produced by the respiratory epithelium and secreted in the airway. In vitro SP-A enhanced phagocytosis and killing of microbial pathogens. To directly determine the role of SP-A in vivo, gene targeted mice lacking SP-A (SP- A-/-) were generated. SP-A (-/-) mice are susceptible to bacterial infection. The present application tests the hypothesis that viral infection alters surfactant phospholipid and protein concentrations and SP-A protects the lung from viral infection in vivo by protecting respiratory epithelial cells from infection and enhancing phagocytosis and modulating synthesis of free radicals by alveolar macrophages. To determine the role of SP-A in lung defense, experiments will determine if SP-A protects mice in vivo from respiratory syncytial virus (RSV) infection. To determine viral clearance mechanisms modulated by SP-A, RSV phagocytosis and generation of oxygen and nitrogen radicals by alveolar macrophages will be assessed in the presence and absence of SP- A. This application will determine the role and delineate mechanisms by which SP-A provides innate immunity to prevent RSV infections. Such data may be useful in the future in designing treatment and prevention of viral pneumonia in susceptible patients. The principle investigator for this proposal has completed a fellowship in critical care medicine and is currently a Research Instructor in the Division of Pulmonary Biology, Department of Pediatrics. Throughout her training, she has demonstrated a continued interest in and ability to accomplish basic science investigation. The RCA will allow the PI to continue to develop in a research environment with many successful independent investigators focused to pulmonary basic science and clinical research. The experimental design on this proposal includes challenging but, particularly in this environment, achievable goals that will provide important knowledge to the understanding of acute lung injury and host defense of the lung.