Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract illness in children. The primary site of RSV infection is the airway epithelium and it is associated with a predominance of neutrophils in bronchoalveolar lavage fluid. The presence of neutrophils in the airways is paralleled by increased amounts of IL-8, a potent chemotactic factor for neutrophils. An interesting clinical feature of RSV infection is that it is followed by an increase in airway reactivity. Relevant to this program, this increased airway reactivity includes a greater response to endotoxin-containing dusts. In our preliminary studies, we found that airway epithelium does not respond to endotoxin by releasing IL-8. If the epithelium is infected with RSV, however, there is a marked increased in the release of IL-8 when endotoxin is added to the monolayers. Based on these observations, we hypothesized that RSV infection up-regulates the response of airway epithelium to endotoxin. Since we cannot study all of the relevant mechanisms as they relate to this hypothesis, we decided to ask the following questions: 1) Does RSV infection up-regulate the response to endotoxin in airway epithelium? 2) Does the RSV-induced response to endotoxin result in upregulation of critical mitogen-activated protein kinase (MAPK) pathways? 3) Is the activation of these MAPK pathways linked to the activation of specific transcription factors that regulate IL-8 gene expression? 4) Hoe is the p42/44 kinase activated by RSV infection? These observations are likely to have important clinical implications for the pathogenesis of airway inflammation in children who have RSV infections and are exposed to dusts containing endotoxin. These observations also might suggest an interaction between viral infections and a variety of environmental exposures in the pathogenesis of airway inflammation and, possibly, asthma.
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