NON-IMMUNOLOGIC ACTIVATION-SECRETION COUPLING IN MAST CELLS

肥大单元可以同时被视为最好的和 免疫系统中了解最少的组成部分。传统上， 肥大细胞在免疫球蛋白依赖即刻中的作用 过敏性事件。这一点已经被证明是不合理的 怀疑。相反，垫细胞现在似乎参与了各种各样的活动。 在免疫球蛋白E不明显的疾病中的生物学反应 角色。在这里，精准的肥大细胞触发事件、分泌产物 产生或释放，它们的药理调节在很大程度上仍然存在 默默无闻。 这项建议的长期目标是勾勒出 筛选出生物活性多肽对鼠类纯化种群的影响 结缔组织肥大细胞及其对这些作用的调节 治疗过敏/炎症性疾病的药物 精神错乱。初步实验结果表明，它具有生物活性。 包括生长抑素、缓激肽、神经降压素、P物质和 神经肽Y诱导肥大细胞释放预形成的介质 作为唯一的细胞刺激剂。结果还表明， 肽能和IgE依赖的激活途径不同，并且 提示存在多条肥大细胞触发通路。 调查将集中在结缔组织肥大的使用上 细胞探索新的多肽介导的激活和相似性 与IgE介导的分泌机制相比较时的差异。建议 实验旨在确定药物的剂量依赖性特征。 肽能肥大细胞刺激、花生四烯酸释放和 代谢、多肽诱导的细胞因子释放与药物调节 不同类别代表性药物对多肽的释放 用于治疗过敏/炎症的化合物。 成功完成这些拟议的实验应有助于 对IgE非依赖性调节肥大细胞活性的认识 药理数据可以作为设计更多药物的指南 肥大细胞疾病的成功治疗方法 发挥作用。

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.