The mast cell can simultaneously be viewed as both one of the best and least understood components of the immune system. Traditionally, the role of the mast cell was that of effector in IgE-dependent immediate hypersensitivity events. This has been established beyond reasonable doubt. Conversely, mat cells now appear to participate in a wide variety of biological responses in diseases in which IgE has no demonstrable role. Here, the precise mast cell triggering events, secretory products generated or released and their pharmacological modulation remain largely obscure. The long term objective of this proposal is to delineate effects of selected bioactive peptides upon purified populations of rodent connective tissue mast cells and modulation of these effects by pharmacologic agents used in treatment of allergic/inflammatory disorders. Results of preliminary experiments indicate that bioactive peptides including somatostatin, bradykinin, neurotensin, substance P and neuropeptide Y elicit release of preformed mediators from mast cells when provided as the sole cell stimulant. Results also indicated that peptidergic and IgE dependent activation pathways differ and are suggestive of multiple mast cell triggering pathways. Investigations will focus on the use of connective tissue mast cells to explore novel peptide-mediated activation and similarities and differences when compared to IgE mediated secretory mechanisms. Proposed experiments are designed to determine characteristics of dose-dependent peptidergic mast cell stimulation, arachidonic acid release and metabolism, peptide-induced cytokine release and pharmacologic modulation of peptide-mediated release by representative drugs from various classes of compounds used in treatment of allergy/inflammation. Successful completion of these proposed experiments should contribute to understanding of IgE independent regulation of mast cell activity and pharmacologic data could serve as a guide in the design of more successful approaches toward treatment of diseases in which mast cells play a role.
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