CYTOKINES/ENDOTHELIAL ADHESION MOLECULES IN HAPTEN INDUCED AIRWAY HYPERRESPONSE

低分子半抗原是职业性和其他形式的重要原因 哮喘的症状。它们被认为通过炎症来调节它们的影响。 和免疫机制。调停的致病事件 半抗原致敏的炎症反应和功能失调 然而，暴露在病毒中的个人定义不明确。要解决这些问题 事件我们已经建立了半抗原哮喘的模型 苦味氯化物。在这个模式中，适当地敏感和挑战 小鼠出现晚期呼吸道阻力增加，近100- 折叠式增加呼吸道反应性。这种反应性可以被采用 通过抗原特异性淋巴细胞群转移到幼鼠体内 并与T细胞的粘膜下浸润有关，单个核细胞 细胞和中性粒细胞。我们认为，这一炎症过程 调解我们已经看到的功能变化。我们假设 这些炎症细胞产生特定的细胞因子，从而诱导 表达一种特定模式的内皮细胞黏附分子 允许调节呼吸道的炎性细胞的招募 功能障碍。我们建议： 1)描述在呼吸道中发展的炎症过程 在抗原挑战和/或直接细胞转移之后。我们会 描述炎症反应、时间进程和位置 细胞因子基因在浸润性和固有肺细胞中的表达 内皮细胞黏附分子的表达模式及其研究进展 呼吸道高反应性(AHR)。 2)选择性地干扰当地的特定人员招募 炎症细胞通过影响细胞因子反应进入呼吸道 和/或内皮细胞黏附分子的表达，并检测其影响 在炎症和AHR的发展上的这些操纵。我们 将使用细胞因子受体基因敲除小鼠的骨髓来完成这项工作 野生型或受体缺陷的嵌合小鼠 P-选择素或α-选择素抗体处理的供体细胞和小鼠 VCAM-1的小分子抑制剂。 3)比较细胞因子黏附分子的模式和位置 人半抗原在小鼠半抗原模型中的表达 诱导性异氰酸酯哮喘。细胞因子和细胞因子的模式和位置 黏附分子在小鼠模型和人体组织中的表达 被比较。 对这一独特模型的分析总结了许多小鼠的情况 人类哮喘的特征将使人们能够更准确地定义哮喘 细胞间相互作用导致半抗原诱导的发展 哮喘的呼吸道高反应性。

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.