LEUKOCYTE ADHESION IN ALLERGIC INFLAMMATION

过敏性炎症中的白细胞粘附

• 批准号: 2672320
• 负责人: P. SRIRAMARAO
• 金额: $ 9.39万
• 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 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2672320
• 关键词: antiinflammatory agents; colony stimulating factor; eosinophil; histamine; human tissue; hypersensitivity; integrins; interleukin 1; interleukin 4; intravital microscopy; laboratory rabbit; leukocyte adhesion molecules; platelet activating factor; receptor expression; selectins; smoking; vascular endothelium

Adherence of circulating eosinophils to the vascular endothelium and their accumulation at extravascular sites in inflamed tissues is a hallmark of allergic inflammation. However, the molecular mechanisms mediating eosinophil adhesion under conditions of flow in vivo are not well understood. Recent studies on neutrophils have shown that intravascular adhesion of these cells is a multi-step process involving distinct adhesion and activation steps. Adhesion molecules include members of the selectin family and beta2 integrins which promote neutrophil rolling and subsequent extravasation. We have recently observed that eosinophils from atopic patients similarly roll and adhere to IL-1 stimulated endothelial cells at shear rates. We have found that a beta1 integrin, VLA-4, in addition to L-selectin promotes early events of human eosinophil adhesion to endothelial cells in vivo. The aim of the proposed research is to elucidate the functional role of adhesion receptors in mediating human eosinophil interaction with vascular adhesion molecules in vivo. Using intravital microscopy we will (1) examine the role of L-selectin and VLA-4 integrin in promoting human eosinophil rolling along IL-1 or IL-4 stimulated endothelial cells in vivo. Using anti-VLA-4 and L-selectin antibodies and cell lines transfected with cDNA for human VLA-4 we will determine if both receptors function sequentially or in parallel to promote eosinophil rolling; (2) determine the effects of eosinophil-active cytokines, IL-5 and GM-CSF, on receptor activation and in vivo adhesion of circulating eosinophils (3) examine the effect of chemokines, RANTES, GM- CSF and PAF on receptor mediated firm adhesion (sticking) and subsequent extravasation of normodense and hypodense subpopulations across cytokine stimulated mesenteric EC in vivo and (4) determine the role of histamine, GM-CSF, IL-1, IL-4 and IL-5 on expression of inducible vascular endothelial surface ligands and their role in promoting rolling, sticking and transendothelial migration of activated eosinophils at physiological shear rates in vivo. The surface expression of vascular adhesion molecules in the mesentery under conditions of flow will be correlated with the in vivo function of human eosinophils. These proposed studies are intended to give a better understanding of molecular mechanisms mediating cell adhesion and provide a basis for examining therapeutic strategies for the treatment of allergic inflammation.

循环中嗜酸性粒细胞与血管内皮细胞的粘附及其意义 在发炎组织中血管外部位的积聚是 过敏性炎症然而， 在体内流动条件下嗜酸性粒细胞的粘附并不好 明白最近对中性粒细胞的研究表明，血管内 这些细胞的粘附是一个多步骤的过程， 粘合和活化步骤。粘附分子包括粘附分子的成员。 选择素家族和β 2整联蛋白，其促进嗜中性粒细胞滚动， 随后的溢出。我们最近观察到， 特应性患者类似地滚动并粘附于IL-1刺激的内皮细胞上。 剪切速率下的细胞。我们已经发现，β 1整合素，VLA-4， 添加L-选择素促进人嗜酸性粒细胞粘附的早期事件 到体内的内皮细胞。拟议研究的目的是 阐明粘附受体在介导人类免疫应答中的功能作用。 嗜酸性粒细胞与血管粘附分子的体内相互作用。使用 活体显微镜检查我们将（1）检查L-选择素和VLA-4的作用 整合素促进人嗜酸性粒细胞沿着IL-1或IL-4滚动 在体内刺激内皮细胞。使用抗VLA-4和L-选择素 我们将用人VLA-4的cDNA转染抗体和细胞系， 确定这两种受体是否顺序或平行发挥作用， 促进嗜酸性粒细胞滚动;（2）确定嗜酸性粒细胞活性的影响 细胞因子IL-5和GM-CSF对受体活化和体内粘附的影响 循环嗜酸性粒细胞（3）检查趋化因子，RANTES，GM- CSF和PAF对受体介导的牢固粘附（粘附）和随后的 正常密度和低密度亚群跨细胞因子外渗 在体刺激肠系膜EC和（4）确定组胺的作用， GM-CSF、IL-1、IL-4和IL-5对诱导型血管内皮细胞表达的影响 内皮细胞表面配体及其在促进滚动、粘附 和活化的嗜酸性粒细胞在生理条件下的跨内皮迁移 体内剪切速率。 血管粘连的表面表达 在流动条件下肠系膜中的分子 与人嗜酸性粒细胞的体内功能有关。 这些研究建议 旨在更好地理解分子机制 介导细胞粘附，并为检查治疗性 过敏性炎症的治疗策略。