MECHANISMS OF PROGRAMED CELL DEATH IN EOSINOPHILS

嗜酸性粒细胞程序性细胞死亡的机制

• 批准号: 6030394
• 负责人: JAMES G ZANGRILLI
• 金额: $ 10.22万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6030394
• 关键词: BCL2 gene /protein; CD95 molecule; apoptosis; asthma; cell growth regulation; clinical research; cysteine endopeptidases; eosinophil; eosinophilia; glucocorticoids; human subject; inflammation; interleukin 5; tissue /cell culture

DESCRIPTION (Adapted from applicants' abstract) Airway eosinophilia is a prominent feature of the inflammation in asthma, and current evidence suggests that these cells contribute significantly to asthma pathogenesis. The focus of the PI's research experience to date has been the study of the cellular and humoral events which take place in the asthmatic airway during IgE-mediated inflammation, using the model of segmental antigen challenge in humans. The motivation for writing this application is based upon several in vivo and in vitro observations derived from these studies, namely the presence of prolonged airway eosinophilia in late phase asthmatics, and the differential viability characteristics between airway and circulating eosinophils in culture. This suggests that apoptotic pathways are suppressed/ impaired during eosinophilic inflammation. The mechanisms by which the life span of an eosinophil is regulated at the site of allergic inflammation are unclear at present. They must include factors that promote cell survival initially, and factors that trigger the programmed cell death pathway, ultimately. Eosinophils spontaneously undergo apoptosis when removed from the circulation, but will respond to specific cytokines, such as IL-5, with a marked prolongation in viability. In contrast, programmed cell death in eosinophils is accelerated by treatment with glucocorticoids, or cross linking of surface Fas-antigen which these cells have recently been found to express. The molecular mechanisms underlying Fas- and glucocorticoid-mediated killing of eosinophils, and the extent to which they are active in vivo, are unknown. Significantly, killing by glucocorticoids, but not by Fas engagement, is antagonized by IL-5 suggesting that these agents act at different levels of the cell death pathway. Certain proteins have emerged as critical regulators of apoptosis and include the pro-apoptotic Ced-3-related cysteine proteases (caspases), and anti-apoptotic factors such as Bcl-2. The applicants hypothesize that substances which accelerate eosinophil apoptosis (i.e. glucocorticoids or Fas activation), act by altering the balance or the activity of these apoptotic regulators, particularly the cysteine proteases and associated molecules. They further hypothesize that because eosinophils are exquisitely sensitive to Fas-mediated killing, this must represent a physiologic mechanism by which eosinophilia is controlled during IgE-mediated inflammation in vivo. (End of Abstract)

描述 (改编自申请者摘要)航空嗜酸性粒细胞增多症是一个突出的 哮喘的炎症特征，目前的证据表明 这些细胞在哮喘发病机制中起着重要作用。的关注点 到目前为止，PI的研究经验一直是对细胞和 IgE介导的哮喘气道中的体液事件 炎症，使用节段性抗原攻击人类的模型。这个 编写此应用程序的动机是基于体内和体内的几个 来自这些研究的体外观察，即存在 晚期哮喘患者呼吸道嗜酸性粒细胞增多时间延长及其区别 慢性阻塞性肺疾病患者气道和循环中嗜酸性粒细胞活性特征 文化。这表明细胞凋亡途径受到抑制/损害。 在嗜酸性炎症期间。人类生命周期的机制 变态反应性炎症部位是否调节嗜酸性粒细胞尚不清楚 目前。它们必须包括最初促进细胞存活的因素， 以及最终触发程序化细胞死亡途径的因素。 当嗜酸性粒细胞从外周血中移出时，会自发地发生凋亡。 循环，但会对特定的细胞因子，如IL-5，通过 生存能力显著延长。相比之下，程序性细胞死亡在 用糖皮质激素或CROSS治疗可加速嗜酸性粒细胞 这些细胞最近发现的表面Fas抗原的连接 快递。Fas-和Fas-2的分子机制 糖皮质激素介导的嗜酸性粒细胞杀伤及其程度 在活体内是活跃的，是未知的。值得注意的是，糖皮质激素会导致死亡， 但不是因为Fas的参与，而是被IL-5拮抗，这表明这些 药物作用于细胞死亡途径的不同层面。某些蛋白质 已经成为细胞凋亡的关键调节因子，包括 促凋亡的Ced-3相关半胱氨酸蛋白酶(Caspase)，以及 抗细胞凋亡因子，如Bcl2。申请者假设 促进嗜酸性粒细胞凋亡的物质(即糖皮质激素或 Fas激活)，通过改变这些细胞的平衡或活动来起作用 细胞凋亡调节因子，特别是半胱氨酸蛋白酶和相关的 分子。他们进一步假设，因为嗜酸性粒细胞 对Fas介导的杀戮极其敏感，这一定代表着 控制嗜酸性粒细胞增多症的生理机制 免疫球蛋白介导的体内炎症反应。(摘要结束)