CHEMICAL MEDIATORS OF ACUTE PULMONARY DISORDERS

这一合作努力的主要目标仍然是 从生理、细胞和分子角度描述这些因素 它调节肥大细胞的发育和功能。把这些因素加在一起 创造一个具有多种组织相关表型的多效性细胞。 尽管肥大细胞起源于骨髓干细胞，并呈现 在表型截然不同的组织部位，中间体 表型分布于组织或在组织内发育到 提供了与组织相关的成熟表型，有待阐明。 组织培养系统，从骨髓干细胞开始，将 继续用于定义调节表型的调节事件。 重组肥大细胞缺陷动物的平行研究 将使用适当的分子和免疫学探针来识别 骨髓、血液和/或淋巴中的早期肥大细胞前体细胞，以及 评估多个部位肥大细胞的后续发育情况 中性蛋白水解酶表达的组织导向变化术语 和细胞因子。因为肥大细胞有能力产生 膜衍生花生四烯酸白三烯的克隆目标 LTC4合成酶的cDNA和基因继续存在，从而使LTC4合成酶的调节 在IgE中可以更全面地研究这一途径中涉及的步骤- 依赖的肥大细胞系统，或在先前开发的细胞因子中 调节人类嗜酸性粒细胞系统。肥大细胞在启动中的作用 小鼠呼吸道对乙酰甲胆碱的增强反应性，将是 通过修改肥大细胞表型来解决，或者使用药理学 抑制或基因破坏以消除中性蛋白酶。这个 与自然发生的呼吸道相关的遗传基因座 不同品系的小鼠的高反应性将用 连锁分析。这些研究将描绘出以下因素： 肥大细胞的发育、分布和表型；与表型相关 花生四烯酸在离散蛋白水解酶中的作用 代谢和细胞因子的产生；最后，与表型相关 在小鼠模型中对呼吸道反应性的作用。

The major objective of this collaborative effort continues to be to characterize, in physiological, cellular and molecular terms, the factors that regulate mast cell development and function. Together these factors act to create a pleiotropic cell with several tissue-related phenotypes. Although the mast cell arises from bone marrow stem cells, and presents at tissue sites in phenotypically distinct forms, the intermediate phenotype distributed to the tissues or developing within the tissue to provide the tissue-related mature phenotype, remain to be elucidated. Tissue culture systems, beginning with the bone marrow stem cell, will continue to be used to define the regulatory events modulating phenotype. Parallel studies in reconstituted mast cell deficient animals with the appropriate molecular and immunologic probes will be used to identify early mast cell progenitors in bone marrow, blood and/or lymph, and to assess the subsequent development of mast cells at multiple sites in terms of tissue-directed changes in the expression of neutral proteases and cytokines. As the mast cell possesses the capacity to produce leukotrienes from membrane-derived arachidonic acid, the goal of cloning the cDNA and gene for LTC4 synthase continues, so that the regulation of the steps involved in this pathway can be more fully studied in IgE- dependent mast cell systems, or in the previously developed cytokine regulated human eosinophil system. The role of the mast cell in priming the mouse airway for augmented reactivity to methacholine, will be addressed by modifying mast cell phenotypes, either using pharmacologic inhibition or gene disruption to eliminate neutral proteases. The genetic loci associated with naturally occurring airway hyperresponsiveness in various murine strains will be probed using linkage analysis. The studies will delineate the factors that define mast cell development, distribution, and phenotype; phenotype-related functions in the areas of discrete protease action, arachidonic acid metabolism and cytokine generation; and, finally, phenotype-related functions directed to airway reactivity in the mouse model.