CYTOKINES/ENDOTHELIAL ADHESION MOLECULES IN HAPTEN INDUCED AIRWAY HYPERRESPONSE

半抗原诱导的气道高反应中的细胞因子/内皮粘附分子

• 批准号: 6110672
• 负责人: GREGORY P GEBA
• 金额: $ 18.7万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6110672
• 关键词: asthma; cell adhesion molecules; cell transplantation; chemical hypersensitivity; cytokine; cytokine receptors; disease /disorder model; gene targeting; haptens; human tissue; inflammation; isocyanates; laboratory mouse; molecular pathology; respiratory epithelium; respiratory hypersensitivity; selectins

Low molecular haptens are import causes of occupational and other forms of asthma. They are presumed to mediate their effects via inflammatory and immune mechanisms. The pathogenetic events that mediate inflammation and functional dysregulation in hapten sensitized and exposed individuals, however, are poorly defined. To address these events we have established a model of hapten asthma using picrylchloride. In this model, appropriately sensitized and challenged mice develop late phase increases in airways resistance and nearly 100- fold increases in airway reactivity. This reactivity can be adoptively transferred to naive mice by antigen-specific populations of lymphocytes and is associated with submucosal infiltration by T cells, mononuclear cells and neutrophils. We believe that this inflammatory process mediates the functional changes that we have seen. We hypothesize that these inflammatory cells produce specific cytokines which induce the expression of a specific pattern of endothelial adhesion molecules which allows for the recruitment of inflammatory cells that mediate airway dysfunction. We propose to: 1) Characterize the inflammatory process that develops in the airway following antigen challenge and/or direct cell transfer. We will characterize the inflammatory response, the time course and location of cytokine gene expression by infiltrating and intrinsic lung cells, the pattern of endothelial adhesion molecule expression and the development of airways hyperresponsiveness (AHR). 2) Selectively interfere with the local recruitment of specific inflammatory cells to the airway by influencing cytokine responses and/or endothelial adhesion molecule expression and examine the effects of these manipulations on the development of inflammation and AHR. We will do this using cytokine receptor knock-out mice, bone marrow chimeric mice reconstituted with either wild-type or receptor deficient donor cells and mice treated with antibodies against P-selectin or a small molecule inhibitor to VCAM-1. 3) Compare the patterns and locations of cytokine adhesion molecule expression in the mouse hapten model to biopsies from human hapten- induced isocyanate asthma. The pattern and location of cytokine and adhesion molecule expression in the murine model and human tissues will be compared. The analysis of this unique model which recapitulates in mice many of the features of human asthma will allow a more precise definition of the cellular interactions leading to the development of hapten-induced asthmatic airway hyperreactivity.

低分子触觉是职业和其他形式的进口原因 哮喘。 假定他们通过炎症调解其影响 和免疫机制。 介导的致病事件 触觉敏感的炎症和功能失调， 但是，暴露的个体的定义很差。 解决这些 我们已经建立了一种使用的模型使用 苦瓜氯化物。 在此模型中，适当敏感和挑战 小鼠在抗气道阻力和近100次的后期增加。 气道反应性的折叠增加。 这种反应性可以很顺序 由淋巴细胞的抗原特异性种群转移到天真小鼠中 并且与T细胞，单核浸润有关 细胞和中性粒细胞。 我们相信这种炎症过程 调解我们所看到的功能变化。 我们假设这一点 这些炎性细胞产生特定的细胞因子，诱导 内皮粘附分子的特定模式的表达 允许募集介导气道的炎症细胞 功能障碍。 我们建议： 1）表征气道中发生的炎症过程 抗原挑战和/或直接细胞转移。 我们将 表征炎症反应，时间过程和位置 细胞因子基因表达通过浸润和内在的肺细胞， 内皮粘附分子表达和发育的模式 气道高反应性（AHR）。 2）选择性干扰特定的本地招聘 通过影响细胞因子反应到气道的炎症细胞 和/或内皮粘附分子表达并检查效果 这些关于炎症和AHR发展的操纵。 我们 将使用细胞因子受体敲除小鼠，骨髓来执行此操作 用野生型或受体不足的嵌合小鼠重构 用抗P-选择素或A的抗体处理的供体细胞和小鼠 小分子抑制剂至VCAM-1。 3）比较细胞因子粘附分子的模式和位置 小鼠触发模型中的表达对人类触觉的活检 诱导异氰酸酯哮喘。 细胞因子的模式和位置​​以及 鼠模型和人体组织中的粘附分子表达将 比较。 对这种独特模型的分析，该模型概括了小鼠的许多模型 人类哮喘的特征将允许对 细胞相互作用导致触觉诱导的 哮喘气道高反应性。