LEUCOCYTE ADHESION IN ALLERGIC INFLAMMATION

过敏性炎症中的白细胞粘附

• 批准号: 6373379
• 负责人: P. SRIRAMARAO
• 金额: $ 43.96万
• 依托单位: LA JOLLA INST FOR MOLECULAR MEDICINE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6373379
• 关键词: CD44 molecule; bone marrow; cell adhesion; cell migration; chemotaxis; cytokine; eosinophil; gene expression; hematopoietic stem cells; human tissue; inflammation; interleukin 5; intravital microscopy; laboratory mouse; leukocyte adhesion molecules; metalloendopeptidases; monoclonal antibody; vascular cell adhesion molecule; vascular endothelium

Adherence of circulating eosinophil to vascular endothelium and their recruitment to extravascular sites in inflamed tissues is the hallmark of allergic inflammation. Recent studies have identified an important role for adhesion molecules and other mediators in the sequestration of eosinophils to sites of inflammation. In this competing renewal we first postulate that vascular cell adhesion molecule (VCAM-1) is a multifunctional cell adhesion molecule that supports initial rolling, activation dependent stable adhesion and chemokine mediated transmigration of eosinophils by interacting with different activation states of alpha4 integrins. Using VCAM-1 deficient heterozygous mice we will determine the tissue specific contribution of VCAM-1 to eosinophil recruitment to sites of allergic inflammation in the skin and peritoneum. Our studies have identified that CD44 may function as a novel rolling receptor for human eosinophils. Furthermore, C3a appears to function as a eosinophil active chemoattractant to mediate stable adhesion of rolling cells. We will therefore, examine the function of CD44 and C3a in eosinophil mediated allergic inflammation. Since matrix matalloproteinases (MMPs) play an important role in the migration of leukocytes within the extravascular space, we will examine the importance of eosinophil expressed MMP-9 as well as an inducible eosinophil-specific MMP, designated as MMP-E, in mediating eosinophil chemotaxis in vivo as part of the second specific aim. In addition monoclonal antibodies against MMP-E will be generated with a view to better understand the biochemical and functional regulation of MMP-E in the context of eosinophil recruitment and allergic inflammation. Since exposure to cytokines such as IL-5 leads to significant eosinophilia, in the third specific aim, the mechanisms of IL-5/allergen-induced mobilization of hematopoietic progenitor/stem cell (HPSC) and eosinophil committed progenitors in the bone marrow will be investigated. We will also investigate how IL-5 modulates the trafficking/migration of HPSC from the bone marrow microenvironment (stromal and endothelial cells) to distal sites of allergic inflammation (lung endothelial cells under conditions of flow. Using in vivo techniques of intravital microscopy along with in vitro molecular and cellular tools, the proposed studies are intended to give a better understanding of the molecular mechanisms mediating eosinophil interactions in inflamed blood vessels and tissues and to provide a basis for developing novel therapeutic strategies for treatment of allergic inflammation.

循环中的嗜酸性粒细胞黏附于血管内皮细胞，并重新聚集到炎症组织的血管外部位，是过敏性炎症的标志。最近的研究发现，黏附分子和其他介质在将嗜酸性粒细胞隔离到炎症部位的过程中起着重要作用。在这一竞争更新中，我们首先假设血管细胞黏附分子(VCAM-1)是一种多功能细胞黏附分子，通过与α4整合素的不同激活状态相互作用，支持嗜酸性粒细胞的初始滚动、激活依赖的稳定黏附和趋化因子介导的迁移。利用VCAM-1缺陷杂合子小鼠，我们将确定VCAM-1对皮肤和腹膜过敏性炎症部位的嗜酸性粒细胞募集的组织特异性贡献。我们的研究证实，CD44可能是一种新的人类嗜酸性粒细胞滚动受体。此外，C3a似乎作为嗜酸性粒细胞活性趋化剂来调节滚动细胞的稳定黏附。因此，我们将研究CD44和C3a在嗜酸性粒细胞介导的变态反应性炎症中的作用。由于基质金属蛋白酶(MMPs)在白细胞在血管外间隙内的迁移中起重要作用，我们将检测嗜酸性粒细胞表达的基质金属蛋白酶-9以及可诱导的嗜酸性粒细胞特异性基质金属蛋白酶-E在体内介导嗜酸性粒细胞趋化的重要性，作为第二个特定目标的一部分。此外，还将产生抗基质金属蛋白酶-E的单抗，以期更好地了解基质金属蛋白酶-E在嗜酸性粒细胞聚集和过敏性炎症的背景下的生化和功能调节。由于暴露于IL-5等细胞因子会导致明显的嗜酸性粒细胞增多，在第三个特定目的中，我们将研究IL-5/变应原诱导骨髓中造血祖细胞/干细胞(HPSC)和嗜酸性粒细胞定向祖细胞动员的机制。我们还将研究IL-5如何调节HPSC从骨髓微环境(间质和内皮细胞)到过敏性炎症的远端部位(血流条件下的肺内皮细胞)的运输/迁移。利用活体显微镜技术以及体外分子和细胞工具，这些研究旨在更好地了解炎症血管和组织中嗜酸粒细胞相互作用的分子机制，并为开发治疗变态反应性炎症的新的治疗策略提供基础。