Inhibitors of chymase as mast cell-stabilizing agents: Contribution of chymase in the activation of human mast cells

There has long been evidence that inhibitors of chymotryptic proteinases ca n inhibit the degranulation of rodent mast cells, but their actions on huma n mast cells and the contribution of mast cell chymase itself have received little attention. We investigated the ability of the selective chymase inh ibitor Z-Ile-Glu-Pro-Phe-CO2Me and other proteinase inhibitors to inhibit c hymase and cathepsin G activity, and we examined their potential to modulat e the responsiveness of mast cells dispersed from human skin, lung, and ton sil tissues. IgE-dependent histamine release from skin mast cells was inhib ited by up to about 80% after preincubation with Z-Ile-Glu-Pro-Phe-CO2Me (u p to 0.1 mu M), 70% with chymostatin (17 mu M), and 60% with soybean trypsi n inhibitor (0.5 mu M). The mast cell-stabilizing properties of chymase inh ibitors appeared to be greater for skin mast cells than for those from lung , whereas tonsil mast cells were relatively unresponsive. There were marked differences in the time course of responses to inhibitors, and the effect was dependent on the stimulus, with calcium ionophore-induced histamine rel ease being unaffected. Incubation of dispersed skin, lung, or tonsil cells for up to 45 min with purified chymase failed to induce histamine release, although preincubation of cells with chymase was able to suppress IgE-depen dent activation. Chymase could thus contribute to mast cell degranulation a nd after secretion could provide a feedback mechanism to limit this process . Nevertheless, inhibitors of chymase can be potent mast cell stabilizers, particularly in the skin.