Infection of the airways with respiratory syncytial virus (RSV) or human influenza virus is associated with acute airway inflammation in normal children, and may trigger exacerbation of lung disease in children with cystic fibrosis (CF). Little is currently known about the role of epithelial mediators in the interaction between airway epithelium, infectious agents, and inflammatory cells. The in vitro study of airway epithelia has led to the discovery of cellular and molecular mechanisms of airway disease. Preliminary data in this laboratory show that epithelial cells in culture can be infected with RSV, and produce platelet-activating factor (PAF), surface adhesion protein, and inflammatory cytokines as a result. The proposed research is designed to test the hypothesis that airway epithelial cells infected with RSV or human influenza virus produce factors which promote or modulate airway inflammation, and that these factors are more strongly expressed in epithelial cells from populations at risk for severe viral disease. The specific goals of the project are to (1) Establish optimal conditions for infection of airway epithelial cells by RSV and influenza virus. Markers of infection will include virus replication, virus antigen-specific immunofluorescence, and viral mRNA. (2) Measure the effect of viral infection on epithelial production of pro- inflammatory factors including IL-1, IL-6, IL-8, GM-CSF, and platelet- activating factor (PAF). (3) Measure the effect of viral infection of epithelia on production of neutrophil chemotactic factors and factors promoting adherence of neutrophils to epithelial cells, including ICAM-1, GMP-140, and LEC-CAM. (4) Compare the above responses in transformed epithelial cells to those in airway epithelial cells in primary culture, and compare epithelial cells of normal adult origin to those of CF or pediatric origin. The results of these experiments will suggest mechanisms responsible for the initiation and maintenance of airway inflammation by respiratory viruses, in normal airways and in CF or pediatric airways. Hypothetical mechanisms will be readily testable using the model system described, and understanding these mechanisms will ultimately suggest specific anti-inflammatory therapies for these patients.
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