The central role of airway mucus in obstructive lung diseases such as chronic bronchitis and bronchial asthma is well appreciated in clinical and pathologic investigations. Abnormalities in mucus secretion and composition are felt to contribute to the morbidity and mortality in these diseases. But the mechanisms controlling the composition of mucus as well as the amount of this secretion remain poorly understood. In previous studies we described a novel molecule, synthesized and released by pulmonary macrophages (PM), peripheral blood monocytes (PMN), and currently from human macrophage hybridoma cell line number 13, which is able to cause human airways to release increased amounts of biosynthetically radiolabeled mucous glycoproteins (MGP). This molecule was termed macrophage (or monocyte) derived mucus secretagogue (MMS). The role of MMS in health and disease forms the basis of this proposal. MMS has been chemically characterized and purified. Initial effort of this proposal will be directed towards the development of immunological assay (ELISA) for the specific and sensitive detection of MMS. This would allow us to investigate the clinical relevance of MMS. Our clinical objectives are to clarify the mechanisms underlying enhanced mucus secretion in patients with bronchitis and chronic obstructive pulmonary disease (COPD). Specifically, we will examine if MMS is important in regulating mucus secretion under these clinical conditions. In vivo and in vitro measurements of MMS activity in PM, PMN and bronchoalveolar lavage fluid (BALF), will be performed in patients with bronchitis and COPD to 1) demonstrate that airway mucus hypersecretion in these clinical conditions is associated with detectable MMS activity; 2) demonstrate that mucus hypersecretion in these patients is associated with macrophage activation leading to facilitated release of MMS; 3) determine the possible mechanisms underlying prolonged mucus secretion in patients with bronchitis and COPD; 4) establish a relation between the hypersecretion of mucus in the airways and MMS activity. We expect that the information derived from these studies will contribute to the understanding of the mechanisms controlling the secretion of airway mucus, especially in patients with mucus hypersecretion. The obtained results may help to identify individuals at risk of developing chronic bronchitis, may provide us with a marker for patients with COPD and will form the basis for pharmacologic intervention in the future.
