MAST-CELLS AND CELL-TO-CELL INTERACTIONS IN AIRWAYS

Dog mastocytomas (anatomic and biochemical features comparable to normal dog and human mast cells) were used to study actions of mast cell mediators on several airway effector systems. We showed mastocytoma cell adherence to both cultured tracheal epithelial cells and tracheal tissue sections for > 48 h that was abolished completely by pretreatment of mast cells with proteases. This mast cell-epithelial cell adhesion-interaction reaction is probably mediated by a mast cell plasma membrane protein. Mast cell mediators stimulate short circuit current and ion flux across dog tracheal epithelia mounted in Ussing chambers. Pretreatment of epithelia with indomethacin blocks this effect, probably by inhibiting LTC4-induced activation of epithelial cyclooxygenases. Mastocytoma cells also increase secretion from cultured serous submucosal gland cells. Blockade of cyclooxygenase and lipoxygenase pathways in mastocytoma cells activated by calcium ionophore does not alter secretion of the serous cells induced by mastocytoma supernatant, but secretion induced by mastocytoma supernatant or purified mast cell chymase is markedly reduced by an inhibitor of chymase. These results suggest that mast cells can alter airway secretions not only by actions on ion flux in epithelial cells but also by actions on submucosal gland secretion; this latter action appears to be mediated by mast cell chymase. Finally, supernatants from mastocytoma cells stimulated by calcium ionophore greatly increase the sensitivity and magnitude of the contractile response of dog bronchial smooth muscle to histamine. These effects are blocked by an inhibitor of mast cell tryptase. Contractions caused by the combination of exogenous histamine and purified mast cell tryptase are abolished by the calcium channel blockers nifedipine and verapamil; however, contraction by acetylcholine, which is independent of calcium channels, is unaffected by tryptase or mastocytoma supernatant, suggesting that mast cell tryptase modifies membrane potential-dependent contractile mechanisms involving calcium channels in bronchial muscle. Thus, tryptase, released with histamine from mast cell granules, may play a dominant role in production of bronchial hyperresponsiveness. In summary, studies of dog mastocytoma cells have enabled us to determine the mechanisms by which mast cell mediators may alter airway secretions and bronchomotor tone during inflammatory reactions of airways.