Redrup, Angela Carol; (1995) The role of chloride ions in histamine secretion from mast cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The mast cell has been implicated in the pathogenesis of a number of allergic diseases, including asthma. Recent studies have indicated that chloride ions may have a functional role in mast cell activation and, therefore, the aim of this study was to examine the role of chloride ions in mast cell secretion. The initial experiments on unpurified rat peritoneal mast cells (RPMC) showed that the immunologically directed ligand, antibody to immunoglobulin E (anti-IgE), required extracellular chloride ions for optimum histamine secretion. In contrast, replacement of extracellular chloride did not alter the mast cell secretory response to the non- immunological secretagogues, compound 48/80, calcium ionophore A23187 and substance P. Radiotracer studies on purified RPMC using the isotope, 36chloride, found that anti-IgE-stimulation evoked a rapid and significant uptake of chloride ions compared to non-stimulated cells. The magnitude of the induced chloride uptake correlated significantly with the magnitude of the stimulated histamine secretion. Other mast cell secretagogues failed to induce chloride uptake but still caused significant RPMC degranulation. These findings were consistent with the initial extracellular chloride replacement studies. The chloride channel blocker, 5-nitro-2-((3-phenylpropyl)-amino)-benzoic acid (NPPB) dose-dependently inhibited both anti-IgE-stimulated chloride uptake into RPMC and histamine secretion from RPMC. This suggests that chloride uptake may occur via chloride channels. The Na+/K+/2C1- cotransport inhibitor, furosemide, lowered anti-IgE-induced chloride uptake at a relatively high concentration, although the more potent Na+/K+/2C1- cotransport inhibitors bumetanide and piretanide had no effect. This indicates that the Na+/K+/2C1- cotransport system is not involved in mast cell secretion. However, the three drugs did had have distinct modulatory actions on histamine secretion from a variety of activated mast cell types. In addition, furosemide was found to have a similar inhibitory profile to the anti-asthma drug, disodium cromoglycate. These two compounds may, therefore, stabilise mast cells through similar mechanisms. In conclusion, this study has demonstrated that chloride ions may have a physiologically relevant role in mast cell secretion. Therefore, agents that inhibit mast cell chloride uptake may have beneficial therapeutic effects in mast cell-related diseases.

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