Summary of Work: The tracheobronchial epithelium produces mucins, which protect the epithelium against toxic chemicals and microbial agents.  However, hypersecretion of mucin is a common and often severe complication of many inflammatory diseases of the airways.  The purpose of our studies is to determine factors and mechanisms regulating mucin genes and mucin secretion.  We found that the expression of several mucin genes including MUC2, MUC4, MUC5AC and MUC5B is dependent on the presence of retinol (vitamin A) or it?s major metabolic derivative, retinoic acid (RA).  Addition of RA to RA-deficient cultures ( which no longer express the mucous phenotype), leads to sequential induction of MUC2, MUC5AC, and MUC5B mRNA, respectively, culminating in the full restoration of the mucous phenotype.  Most RA effects are thought to be mediated by the nuclear receptors, RAR and RXR and their isotypes.  Studies with retinoid receptor isotype-selective agonists and antagonists indicated that RA-binding to RAR-alpha is the main, early event in the induction of mucin genes by RA.  RA-binding to RAR-gamma also seems to play a role, albeit a minor one.  RA-binding to other retinoid receptors does not appear to result in activation of mucin genes.  Currently, studies are in progress to identify elements in the MUC5AC promoter region involved in the regulation of MUC5AC expression by RA.  Other studies are aimed at investigating the regulation of mucin gene expression and the secretion of mucin by inflammatory mediators, including TNF-alpha, interleukins and bacterial polysaccharides.  In collaboration with Dr. John Sheehan from the University of Manchester (GB) we showed that the main mucins secreted by cultured human bronchial cells are MUC5AC and MUC5B, which also are the major mucins produced in vivo.