NON-IMMUNOLOGIC ACTIVATION-SECRETION COUPLING IN MAST CELLS

肥大细胞可以同时被看作是最好的， 免疫系统中最不为人所知的组成部分 传统上 肥大细胞在IgE依赖性的 超敏反应事件 这已经超出了合理的范围 疑问 相反，垫细胞现在似乎参与了各种各样的 在疾病中，IgE没有明显的生物反应， 作用 在这里，肥大细胞的精确触发事件，分泌产物 产生或释放，它们的药理学调节在很大程度上 晦涩难懂。 本提案的长期目标是阐明 选择的生物活性肽对纯化的啮齿动物种群的作用 结缔组织肥大细胞和调节这些作用， 用于治疗过敏/炎症的药物 紊乱 初步实验结果表明， 肽，包括生长抑素、缓激肽、神经降压素、P物质和 神经肽Y引起肥大细胞释放预先形成的介质， 作为唯一的细胞刺激物提供。 结果还表明 肽能和IgE依赖性活化途径不同， 提示有多种肥大细胞触发途径 调查将集中在使用结缔组织肥大 细胞探索新的肽介导的激活和相似性， 与IgE介导的分泌机制相比存在差异。 提出 设计实验以确定剂量依赖性的特征， 肽能肥大细胞刺激、花生四烯酸释放和 肽诱导的细胞因子释放和药理学调节 肽介导的各种类型的代表性药物的释放 用于治疗过敏/炎症的化合物。 成功完成这些拟议的实验将有助于 了解IgE对肥大细胞活性的独立调节， 药理学数据可以作为设计更多药物的指导， 治疗肥大细胞 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.