Eosinophil Lipid Bodies in Allergic Inflammation

过敏性炎症中的嗜酸性粒细胞脂质体

基本信息

批准号：
6625959
负责人：
PETER F WELLER
金额：
$ 3.87万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-05-01 至 2005-04-30
项目状态：
已结题

项目摘要

Central to the pathogenesis of allergic diseases are both the recruitment and activation of eosinophils at sites of allergic inflammation. Among mediators pertinent to allergic inflammation, eosinophils are sources of eicosanoids, including cysteinyl leukotrienes. Cysteinyl leukotrienes are both major paracrine mediators of allergic inflammation and, as only recently recognized, autocrine intracellular mediators regulating vesicular transport-mediated release of cytokines, including the allergic disease pertinent cytokine, IL-4, from eosinophil granule stores. Eosinophils and other leukocytes associated in vivo with inflammatory reactions: l) exhibit, as yet poorly understood, "priming" responses, by which these leukocytes respond more prominently to agonists and can generate greater quantities of eicosanoids; and 2) characteristically contain increased numbers of intracellular lipid bodies. In vitro studies have indicated that lipid bodies are highly regulated, inducible organelles and are sites involved in the priming responses for heightened eicosanoid formation by eosinophils and other cells. Although lipid bodies are ubiquitous in eosinophils and leukocytes in vivo associated with inflammation, the formation and function of lipid bodies within eosinophils in vivo in sites of allergic inflammation have never been investigated. The proposed studies will utilize well- established in vivo models of allergic inflammation to investigate mechanisms of eosinophil activation and to test the hypothesis that intracellular lipid body formation is centrally involved in eosinophil activation in inflammatory responses. Studies will investigate eosinophil lipid body formation and functioning in vivo in allergic inflammation, with four specific aims: 1) investigate molecular pathways of eosinophil lipid body formation in murine models of allergic inflammation; 2) characterize inflammation pertinent components of in vivo-elicited murine eosinophil lipid bodies; 3) evaluate functional roles of lipid bodies in eicosanoid generation and autocrine and paracrine signaling in murine eosinophils; and 4) evaluate pathways of lipid body formation as targets for anti-inflammatory/anti- allergic drug development, including specifically investigating the effects of Brazilian rain forest plant-derived bioactive products on lipid body formation and eicosanoid generation. These studies aim to provide new insights into fundamental intracellular mechanisms of eosinophil activation and potentially identify novel anti-inflammatory therapeutic targets. These studies, to be performed in Brazil, will utilize the expertise of Brazilian investigators with in vivo models of allergic inflammation to extend in vitro studies of human eosinophils in NIH grant # RO1 AI20241.

过敏性疾病发病机制的核心是过敏性炎症部位嗜酸性粒细胞的募集和激活。在与过敏性炎症相关的介质中，嗜酸性粒细胞是类二十烷酸的来源，包括半胱氨酰白三烯。半胱氨酰白三烯都是过敏性炎症的主要旁分泌介质，并且最近才认识到，它们是调节囊泡转运介导的细胞因子释放的自分泌细胞内介质，包括来自嗜酸性粒细胞颗粒储存的与过敏性疾病相关的细胞因子IL-4。嗜酸性粒细胞和其他白细胞在体内与炎症反应相关：l)表现出“启动”反应，但目前还知之甚少，通过这种反应，这些白细胞对激动剂的反应更显着，并且可以产生更大量的类二十烷酸； 2)特征性地含有数量增加的细胞内脂质体。体外研究表明，脂质体是高度调控的诱导性细胞器，并且是参与嗜酸性粒细胞和其他细胞增强类二十烷酸形成的引发反应的位点。尽管脂质体普遍存在于与炎症相关的体内嗜酸性粒细胞和白细胞中，但从未研究过体内过敏性炎症部位嗜酸性粒细胞内脂质体的形成和功能。拟议的研究将利用成熟的过敏性炎症体内模型来研究嗜酸性粒细胞活化的机制，并检验细胞内脂体形成主要参与炎症反应中嗜酸性粒细胞活化的假设。研究将调查过敏性炎症中嗜酸性粒细胞脂体的形成和体内功能，有四个具体目标：1）研究过敏性炎症小鼠模型中嗜酸性粒细胞脂体形成的分子途径； 2) 表征体内引发的小鼠嗜酸性粒细胞脂体的炎症相关成分； 3) 评估脂体在类二十烷酸生成以及小鼠嗜酸性粒细胞自分泌和旁分泌信号传导中的功能作用； 4) 评估脂质体形成途径作为抗炎/抗过敏药物开发的目标，包括专门研究巴西雨林植物衍生的生物活性产品对脂质体形成和类二十烷酸生成的影响。这些研究旨在为嗜酸性粒细胞激活的基本细胞内机制提供新的见解，并可能确定新的抗炎治疗靶点。这些研究将在巴西进行，将利用巴西研究人员在过敏性炎症体内模型方面的专业知识，在 NIH 拨款 # RO1 AI20241 中扩展人类嗜酸性粒细胞的体外研究。