LEUCOCYTE ADHESION IN ALLERGIC INFLAMMATION

过敏性炎症中的白细胞粘附

• 批准号: 6757228
• 负责人: P. SRIRAMARAO
• 金额: $ 41.46万
• 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 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6757228
• 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.

循环嗜酸性粒细胞粘附于血管内皮并募集至发炎组织的血管外位点是过敏性炎症的标志。 最近的研究已经确定了粘附分子和其他介质在将嗜酸性粒细胞隔离到炎症部位中的重要作用。 在这种竞争性更新中，我们首先假设血管细胞粘附分子（VCAM-1）是一种多功能细胞粘附分子，通过与α4整联蛋白的不同激活状态相互作用，支持初始滚动、激活依赖性稳定粘附和趋化因子介导的嗜酸性粒细胞迁移。 使用 VCAM-1 缺陷杂合小鼠，我们将确定 VCAM-1 对嗜酸性粒细胞募集到皮肤和腹膜过敏性炎症部位的组织特异性贡献。 我们的研究发现 CD44 可能作为人类嗜酸性粒细胞的新型滚动受体。此外，C3a 似乎充当嗜酸性粒细胞活性化学引诱剂，介导滚动细胞的稳定粘附。 因此，我们将检查 CD44 和 C3a 在嗜酸性粒细胞介导的过敏性炎症中的功能。 由于基质金属蛋白酶 (MMP) 在白细胞在血管外空间内的迁移中发挥重要作用，作为第二个具体目标的一部分，我们将检查嗜酸性粒细胞表达的 MMP-9 以及可诱导的嗜酸性粒细胞特异性 MMP（称为 MMP-E）在体内介导嗜酸性粒细胞趋化性中的重要性。此外，还将产生针对 MMP-E 的单克隆抗体，以便更好地了解 MMP-E 在嗜酸性粒细胞募集和过敏性炎症背景下的生化和功能调节。 由于暴露于IL-5等细胞因子会导致显着的嗜酸性粒细胞增多，因此在第三个具体目标中，将研究IL-5/过敏原诱导的造血祖细胞/干细胞（HPSC）和骨髓中嗜酸性粒细胞定型祖细胞的动员机制。 我们还将研究IL-5如何调节HPSC从骨髓微环境（基质细胞和内皮细胞）到过敏性炎症远端部位（流动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，拟议的研究旨在更好地理解分子 介导炎症血管和组织中嗜酸性粒细胞相互作用的机制，并为开发治疗过敏性炎症的新治疗策略提供基础。