ROLE OF MAST-CELL AND NEUTROPHIL PROTEASES IN AIRWAY SECRETION

To investigate the hypothesis that mast cell and neutrophil proteases stimulate airway gland secretion, we studied the effects of two mast cell proteases (tryptase and chymase) and two neutrophil enzymes (human neutrophil elastase and cathepsin G) on secretion of S-35-labeled macro-molecules from cultured bovine airway gland serous cells. Tryptase had no effect, but the other three enzymes stimulated secretion. Threshold concentrations of the enzymes (greater-than-or-equal-to 10(-10) M) were lower by two orders of magnitude than other agonists (e.g., histamine, prostaglandins, beta-adrenergic agonists). Only proteases induced maximal secretory response (greater-than-or-equal-to 80% depletion of S-35-labeled macromolecules), and these responses were > 10-fold larger than those of other agonists. The active catalytic sites of the enzymes are required for their secretory activities. These findings suggest a role for these enzymes in the pathogenesis of inflammatory airway diseases associated with hypersecretion, and they suggest that the use of selective site-directed inhibitors of these enzymes may provide a novel strategy for intervention in inflammatory diseases of the airways associated with hypersecretion (e.g., cystic fibrosis, chronic bronchitis).