ENDOTHELIAL CELL MODULATION OF APOPTOSIS IN NEUTROPHILS

内皮细胞对中性粒细胞凋亡的调节

• 批准号: 6602442
• 负责人: T MAYADAS-NORTON
• 金额: $ 6.87万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6602442
• 关键词: apoptosis; cell communication molecule; cell death; human tissue; inflammation; laboratory mouse; leukocyte adhesion molecules; neutrophil; phagocytosis; tissue /cell culture; vascular endothelium

Interaction of neutrophils with the endothelium is important both in the recruitment of neutrophils to the inflamed site and in the modulation of several neutrophil functions. The localized accumulation of functional neutrophils is pivotal in the host's defense against infection and the orderly elimination of these neutrophils is pivotal in the host's defense against infection and the orderly elimination of these neutrophils is important in down-regulation of the inflammatory response. Blood neutrophils are unique among leukocytes in that their circulating half- life is only between 4-10 hours after which they undergo spontaneous apoptosis ("passive cell death") which is associated with the loss of several neutrophil functions and their clearance in the spleen. However, at sites of tissue inflammation, neutrophils have an increased life span and enhanced functional responses compared to circulating neutrophils. Apoptosis of these neutrophils and their engulfment by tissue macrophages is associated with the resolution of inflammation. We have identified two components which regulate the fate of neutrophils at sites of inflammation: cytokine activated endothelium secrete factors which significantly delay the "passive cell death" of neutrophils in vitro and in vivo, while phagocytosis of complement opsonized particles, mediated by the beta2 integrin, Mac-1, triggers rapid apoptosis, a process which we refer to as "phagocytosis induced cell death" (PICD). Our working hypothesis is that the endothelium, which constitutes the interface between blood neutrophils and the tissue actively delays the passive cell death of neutrophils, thereby contributing to the increased pool of functional neutrophils at inflamed sites, and PICD represents an effective mechanism for eliminating neutrophils that have phagocytosed and therefore reached the end of their useful life span. We propose that defects in either component could lead to tissue damage and/or compromised host defense. Dysfunctional up-regulation of the endothelial anti-apoptotic factor(s) could result in increased accumulation of PMNs in the extravascular tissue and prolong the inflammatory response. On the other hand, a reduction in the endothelial derived anti-apoptotic factor(s) could lead to premature apoptosis of neutrophils in the tissue, thereby resulting in compromised host defense. We also postulate that defects in the effector signaling pathways leading to "phagocytosis induced cell death", may induce disease by abrogating apoptosis of neutrophils that have phagocytosed bacteria and cellular debris. Our studies are closely related to the theme of this Program Project. Our overall objective is to investigate the molecular mechanisms involved in communication between endothelial cells and neutrophils to modulate the survival of neutrophils at sites of inflammation. The specific aims of this proposal are to: i) molecularly define the endothelial-derived "anti- apoptotic" factor(s) and determine how the expression of these factor(s) are regulated by endothelial cells; (ii) investigate the intracellular signaling cascades in neutrophils that may transmit the endothelial mediated delay of apoptosis, or Mac-1 triggered apoptosis, and determine how these two mechanisms are related; iii) critically test the biological relevance of the regulation of neutrophil apoptosis in in vivo models of inflammation.

中性粒细胞与内皮细胞的相互作用是重要的， 中性粒细胞向发炎部位的募集以及 几种中性粒细胞功能。功能的局部积累 中性粒细胞在宿主抵抗感染的防御中起关键作用， 这些中性粒细胞的有序清除在宿主的防御中是关键的 抵抗感染，有序地清除这些中性粒细胞， 重要的是下调炎症反应。血液 中性粒细胞在白细胞中是独特的，因为它们的循环半- 生命只有在4 - 10小时之间，之后它们经历自发的 细胞凋亡（"被动细胞死亡"），其与细胞凋亡的丧失有关。 几种中性粒细胞功能及其在脾脏中的清除。然而，在这方面， 在组织炎症部位，中性粒细胞的寿命延长， 并且与循环中性粒细胞相比增强了功能反应。 这些中性粒细胞的凋亡及其被组织巨噬细胞吞噬 与炎症的消退有关。我们已经确定了两个 调节嗜中性粒细胞命运的成分， 炎症：细胞因子激活内皮分泌因子， 显著延迟体外嗜中性粒细胞的"被动细胞死亡"， 在体内，虽然补体调理颗粒的吞噬作用，介导的 β 2整合素，Mac-1，触发快速凋亡，这是一个我们 称为"吞噬作用诱导的细胞死亡"（PICD）。我们的工作 一种假设是，构成界面的内皮细胞 在血液中性粒细胞和组织之间， 中性粒细胞死亡，从而导致 炎症部位的功能性中性粒细胞，PICD代表了有效的 消除吞噬的中性粒细胞的机制， 达到了使用寿命的终点。我们建议， 任何一种成分都可能导致组织损伤和/或宿主受损 防御内皮细胞抗凋亡蛋白的功能失调性上调 因素可能导致PMNs的积聚增加， 并延长炎症反应。另 一方面，内皮源性抗凋亡因子减少 可能导致组织中的中性粒细胞过早凋亡， 导致主机防御受损。我们还假设， 导致"吞噬作用诱导的细胞"的效应器信号传导途径 死亡"，可能通过消除嗜中性粒细胞的凋亡而诱导疾病， 有吞噬的细菌和细胞碎片 我们的研究与这个项目的主题密切相关。我们 总体目标是研究参与的分子机制， 内皮细胞和中性粒细胞之间的通讯，以调节 中性粒细胞在炎症部位的存活。的具体目标 该建议是：i）从分子上定义内皮衍生的"抗- 细胞凋亡"因子，并确定这些因子的表达 由内皮细胞调节;（ii）研究细胞内 嗜中性粒细胞中的信号级联，可能将内皮细胞 介导的细胞凋亡延迟，或Mac-1触发的细胞凋亡，并确定 这两种机制是如何联系在一起的; iii）严格测试生物学 中性粒细胞凋亡的调节在体内模型中的相关性 炎症