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: 6536501
• 负责人: JAMES G ZANGRILLI
• 金额: $ 12.01万
• 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 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6536501
• 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 （改编自申请人的摘要）气道嗜酸性粒细胞增多是一个突出的 哮喘炎症的特征，目前的证据表明 这些细胞对哮喘发病机制有显着影响。 重点是 迄今为止，PI 的研究经验是细胞和 IgE 介导的哮喘气道中发生的体液事件 炎症，使用人类分段抗原攻击模型。 这 编写此应用程序的动机基于体内和体内的一些 从这些研究中得出的体外观察结果，即存在 晚期哮喘患者气道嗜酸性粒细胞增多，以及鉴别诊断 气道和循环嗜酸性粒细胞之间的活力特征 文化。 这表明细胞凋亡途径被抑制/受损 嗜酸性粒细胞炎症期间。 寿命延长的机制 嗜酸性粒细胞在过敏性炎症部位受到调节尚不清楚 现在。 它们必须包括最初促进细胞存活的因素， 以及最终触发程序性细胞死亡途径的因素。 当嗜酸性粒细胞从细胞中取出时，它会自发地发生凋亡。 循环，但会响应特定的细胞因子，例如 IL-5，具有 生存能力显着延长。 相比之下，程序性细胞死亡 糖皮质激素治疗或交叉治疗可加速嗜酸性粒细胞的升高 最近发现这些细胞具有表面 Fas 抗原的连接 表达。 Fas- 和 Fas- 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 体内是否有活性，尚不清楚。 值得注意的是，通过糖皮质激素杀死， 但不是通过 Fas 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水平。 某些蛋白质 已成为细胞凋亡的关键调节因子，包括 促凋亡 Ced-3 相关半胱氨酸蛋白酶（半胱天冬酶），以及 抗凋亡因子如Bcl-2。 申请人假设 加速嗜酸性粒细胞凋亡的物质（即糖皮质激素或 Fas 激活），通过改变这些的平衡或活性来发挥作用 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 介导的杀伤极其敏感，这必须代表 控制嗜酸性粒细胞增多的生理机制 IgE 介导的体内炎症。 （摘要完）