MECHANISMS OF PROGRAMED CELL DEATH IN EOSINOPHILS

描述 （改编自申请人摘要）气道嗜酸性粒细胞增多症是一个突出的 哮喘炎症的特征，目前的证据表明， 这些细胞对哮喘发病机理有重要作用。 的焦点 PI迄今为止的研究经验是研究细胞和 IgE介导的哮喘气道中发生的体液事件 炎症，使用人类节段性抗原攻击模型。 的 撰写本申请的动机是基于几种体内和体内 来自这些研究的体外观察结果，即 晚期哮喘患者气道嗜酸性粒细胞增多症的延长， 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， 嗜酸性粒细胞性炎症 生物体寿命的机制 嗜酸性粒细胞在过敏性炎症部位的调节尚不清楚 目前。 它们必须包括促进细胞存活的因子， 以及最终触发程序性细胞死亡途径的因素。 嗜酸性粒细胞在从外周血中移除时自发地发生凋亡。 循环，但会响应特定的细胞因子，如IL-5，与 生存能力的显著延长。 相比之下， 嗜酸性粒细胞的加速治疗与糖皮质激素，或交叉 最近发现这些细胞的表面Fas抗原的连接， 快车 Fas和Fas受体的分子机制 糖皮质激素介导的嗜酸性粒细胞的杀伤，以及它们在多大程度上 在体内是有活性的，是未知的。 值得注意的是，糖皮质激素的致死作用， 而不是通过Fas的参与，被IL-5拮抗，这表明这些 药剂作用于细胞死亡途径的不同水平。 某些蛋白质 已经成为细胞凋亡的关键调节因子， 促凋亡Ced-3相关半胱氨酸蛋白酶（半胱天冬酶），和 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），通过改变这些细胞的平衡或活性来发挥作用。 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，因为嗜酸性粒细胞是 对Fas介导的杀伤非常敏感，这一定代表了 嗜酸性粒细胞增多症的生理机制， 体内IgE介导的炎症。 (End摘要）

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)