Mucus hyperproduction contributes to morbidity and mortality in patients with chronic airway diseases. In asthma, chronic bronchitis and cystic fibrosis, inflammation is believed to stimulate mucus production, despite their different characteristic airway pathologies. We have defined two inflammatory pathways that lead to mucus production, using a murine system we developed to study the inflammatory effects of Th1 and Th2 cells in the respiratory tract. Th2 cells activated in the airways of mice stimulate airway eosinophilia, airway hyperresponsiveness and mucus production; features found in asthmatic patients. We show that mucus induction by Th2 cells does not require IL-4, IL-5, eosinophils or mast cells, but depends on signaling through IL-4Ralpha, the common chain in IL-13 and IL-4 receptors. Thus, it appears that IL-13 stimulates mucus production induced by Th2 cells. We also show that mucus can be induced by a mechanism that is Th2-independent and associated with airway neutrophilia, suggesting some of the features in chronic bronchitis and cystic fibrosis. We present novel studies showing that Th1 cells, through the production of IFNgamma, inhibit mucus production induced by both Th1 and Th2 cells. Furthermore, IFNgamma produced by Th1 cells has the potential to reduce airway pathology in immunotherapy of asthma. Our goals in this proposal are to gain a more complete understanding of the cellular and molecular mechanisms that regulate mucus production.
Our aims are to 1) determine the mechanism by which CD4 Th cells stimulate mucus production; 2) determine how airway epithelial mucus production is inhibited by IFNgamma 3) determine the extent of inhibitory effects of IFNgamma on mucus production. Using our established adoptive transfer system in which Th1 and Th2 cells and recipient mice can be independently genetically manipulated, the precise factors important in the control of mucus production will be determined.
