CLASSICAL 2ND-MESSENGER ARE NOT INVOLVED IN PROTEINASE-INDUCED DEGRANULATION OF AIRWAY GLAND-CELLS

Neutral serine proteinases such as mast cell chymase, cathepsin G, and neutrophil elastase are far more potent secretagogues for airway glan d serous cells than all other agonists studied (e.g., histamine and br adykinin). To determine the mechanism of proteinase-induced secretion, we investigated the stimulation-secretion coupling in cultured bovine serous cells. Histamine stimulates degranulation of serous cells via adenosine 3',5'-cyclic monophosphate-, protein kinase C-, and intracel lular Ca2+ concentration ([Ca2+](i))-dependent pathways. Similarly, br adykinin-induced secretion involves inositol phosphates, protein kinas e C, and [Ca2+](i). Degranulation caused by both agonists also depends on the activity of an endogenous metalloprotease, which is required i n a late step of stimulation-secretion coupling, i.e., after Ca2+ entr y. On the basis of the effect of different inhibitors, this metallopro tease is a Zn2+- and Ca2+-dependent enzyme similar to a gelatinase A s ynthesized by serous cells. In marked contrast to other secretagogues, degranulation induced by chymase, cathepsin G, and neutrophil elastas e neither involves the classical second messengers nor the activity of the endogenous metalloprotease. These observations suggest that exoge nous proteinases such as chymase, cathepsin CT, and elastase may subst itute for or mimic the action of an endogenous metalloprotease and dir ectly activate degranulation, bypassing the signal transduction mechan isms necessary for secretion caused by other agonists.