TY - JOUR T1 - Inhibitors of Chymase as Mast Cell-Stabilizing Agents: Contribution of Chymase in the Activation of Human Mast Cells JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 517 LP - 523 VL - 291 IS - 2 AU - Shaoheng He AU - Marianna D. A. Gaça AU - Alan R. McEuen AU - Andrew F. Walls Y1 - 1999/11/01 UR - http://jpet.aspetjournals.org/content/291/2/517.abstract N2 - There has long been evidence that inhibitors of chymotryptic proteinases can inhibit the degranulation of rodent mast cells, but their actions on human mast cells and the contribution of mast cell chymase itself have received little attention. We investigated the ability of the selective chymase inhibitor Z-Ile-Glu-Pro-Phe-CO2Me and other proteinase inhibitors to inhibit chymase and cathepsin G activity, and we examined their potential to modulate the responsiveness of mast cells dispersed from human skin, lung, and tonsil tissues. IgE-dependent histamine release from skin mast cells was inhibited by up to about 80% after preincubation with Z-Ile-Glu-Pro-Phe- CO2Me (up to 0.1 μM), 70% with chymostatin (17 μM), and 60% with soybean trypsin inhibitor (0.5 μM). The mast cell-stabilizing properties of chymase inhibitors 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 release 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-dependent activation. Chymase could thus contribute to mast cell degranulation and 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. The American Society for Pharmacology and Experimental Therapeutics ER -