MECHANISMS OF CHEMOKINE-INDUCED INFLAMMATION IN HUMANS

趋化因子引起的人类炎症机制

• 批准号: 6266311
• 负责人: Lisa Ann Beck
• 金额: $ 32.1万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6266311
• 关键词: atopy; chemokine; clinical research; cytokine receptors; eosinophil; epithelium; human subject; human tissue; inflammation; leukocyte activation /transformation; receptor expression; respiratory epithelium; skin

Several members of the C-C branch of the chemokine family have been strongly implicated in the generation of tissue eosinophilia during allergic inflammation, due to their potent and selective chemoattractant activity on eosinophils. Since eosinophils are believed to be responsible for the tissue damage observed in allergic diseases, an improved understanding of the factors responsible for their recruitment in vivo is imperative. We have developed an in vivo chemokine challenge model with which we characterized the tissue response to RANTES in humans. We noted a profound delay in eosinophil recruitment in nonallergic subjects as compared to allergic subjects. Studies described in Aim 1 are designed to test whether the state of eosinophil priming or CCR3 expression or function explain this result. Studies in following Aims will follow up on our recent exciting discovery that epithelial (Aim 2) and endothelial (Aim 3) cells express a functional CCR3, which to date has only been described on leukocytes, mast cells and microglial cells. We will study the regulation of CCR3 expression focusing on cytokine families that are relevant for allergic diseases, namely Th1 and Th2 cytokines. Functional studies will focus on cell migration, induction of adhesion molecule expression, cytokine production and proliferation. To provide further insight into the biology of this receptor, we will determine whether epithelial or endothelial CCR3 expression varies depending on disease status (allergic vs nonallergic ) and whether allergen challenge modulates the baseline expression in allergic subjects. This grant proposal will test the overall hypothesis that chemokine responsiveness in vivo is dependent on several factors. including leukocyte priming and expression and function of relevant chemokine receptors on leukocytes and parenchymal cells (such as epithelial and endothelial cells). Results of these studies are likely to provide insights into the mechanisms by which chemokines induce cutaneous cell recruitment and will likely identify entirely new biological effects of C-C chemokines.

趋化因子家族 C-C 分支的几个成员由于对嗜酸性粒细胞具有有效和选择性的化学引诱活性，因此与过敏性炎症期间组织嗜酸性粒细胞增多的产生密切相关。由于嗜酸性粒细胞被认为是造成过敏性疾病中观察到的组织损伤的原因，因此必须更好地了解嗜酸性粒细胞在体内募集的因素。我们开发了一种体内趋化因子激发模型，通过该模型我们表征了人类对 RANTES 的组织反应。我们注意到与过敏受试者相比，非过敏受试者的嗜酸性粒细胞募集明显延迟。目标 1 中描述的研究旨在测试嗜酸性粒细胞启动状态或 CCR3 表达或功能是否可以解释这一结果。以下目标的研究将延续我们最近令人兴奋的发现，即上皮细胞 (Aim 2) 和内皮细胞 (Aim 3) 表达功能性 CCR3，迄今为止仅在白细胞、肥大细胞和小胶质细胞中进行了描述。我们将研究CCR3表达的调节，重点关注与过敏性疾病相关的细胞因子家族，即Th1和Th2细胞因子。功能研究将集中于细胞迁移、粘附分子表达的诱导、细胞因子的产生和增殖。为了进一步了解该受体的生物学特性，我们将确定上皮或内皮 CCR3 表达是否根据疾病状态（过敏与非过敏）而变化，以及过敏原激发是否调节过敏受试者的基线表达。该拨款提案将检验体内趋化因子反应性取决于多个因素的总体假设。包括白细胞启动以及白细胞和实质细胞（如上皮细胞和内皮细胞）上相关趋化因子受体的表达和功能。这些研究的结果可能会深入了解趋化因子诱导皮肤细胞募集的机制，并可能确定 C-C 趋化因子的全新生物效应。