Rhinovirus induces MUC5AC in a human infection model, and in vitro via NF-{kappa}B and EGFR pathways

Rhinovirus (RV) infections are the major cause of asthma exacerbations - the major cause of morbidity and mortality in asthma. MUC5AC is the major mucin produced by bronchial epithelial cells. Whether RV infection up-regulates MUC5AC in vivo is unknown, and the molecular mechanisms involved incompletely understood. We investigated RV induction of MUC5AC in vivo and in vitro to identify targets for development of new therapies for asthma exacerbations. RV infection increased MUC5AC release in normal and asthmatic volunteers experimentally infected with RV-16; and in asthmatic, but not normal subjects, this was related to virus load. Bronchial epithelial cells were confirmed a source of MUC5AC in vivo. RV induction of MUC5AC in bronchial epithelial cells in vitro occurred via nuclear factor-kappaB dependent induction of matrix metalloproteinase mediated transforming growth factor-alpha release, thereby activating an epidermal growth factor receptor-dependent cascade culminating, via mitogen-activated protein kinase activation, in specificity protein-1 trans-activation of the MUC5AC promoter. RV induction of MUC5AC may be an important mechanism in RV-induced asthma exacerbations in vivo. Revealing the complex serial signalling cascade involved identifies targets for development of pharmacologic intervention to treat mucus hyper secretion in RV induced illness.