Human rhinoviruses are major trigger factors for acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). It is unclear how rhinovirus infections induce disease exacerbations, but the airway epithelial cell is the principal site of rhinovirus infection. Rhinovirus infection does not cause overt epithelial cytotoxicity, so current thinking is that rhinoviruses induced disease by altering epithelial cell biology in a manner that increases airway inflammation. We are using both in vitrostudies with cultured epithelial cells, as well as natural rhinovirus infections in humans to examine the mechanisms by which infected cells produce both host defense molecules, which may protect against viral infections and inflammation, and proinflammatory cytokines that could worsen inflammation. We are trying to determine if the balance between these two responses is critical in determining susceptibility to asthma attacks. Newer studies are extending this work to examine the role of rhinovirus in causing structural changes in the airway, and to examine how cigarette smoking may alter epithelial responses to rhinovirus infections.