COCKROACH ALLERGEN INDUCED AIRWAY INFLAMMATION

尽管我们对这一机制的理解有了很大的提高， 参与哮喘的病理过程，死亡率和发病率 继续上升，尤其是在市中心的儿童中。许多疾病的病因 市中心的哮喘患者似乎与蟑螂传播有关， 过敏原在现时的建议中，我们已进行详细研究， 蟑螂变应原诱导小鼠气道模型的特异性机制 高反应性类似于特应性人类哮喘反应。的 该模型中的过敏反应包括 变应原特异性血清IgE，BAL中组胺的立即释放， 过敏原特异性气道嗜酸性粒细胞增多， 与气道炎症相关的生理学。所述特定聚焦 本建议中的研究将审查 特异性趋化因子在不同阶段诱导气道高反应性 蟑螂过敏原诱导的反应不同反应 过敏性气道疾病的某些阶段似乎围绕着 过敏原再激发时的炎症强度和 特异性趋化因子介导的局部白细胞群的活化。我们 假设利用特异性受体的特异性CC趋化因子 将负责诱导气道高反应性在不同的 蟑螂过敏原诱导的气道反应的阶段。为了验证这一 假设，本提案中概述的研究将检查两个CC 家族趋化因子MCP-1和嗜酸性粒细胞趋化因子，其特异性结合CCR 2， CCR 3，并似乎介导不同的反应，导致 气道高反应性我们的研究将包括以下内容：1） 表征炎症反应和趋化因子表达谱 在过敏反应的不同阶段，2）检查 趋化因子耗竭后的炎症和气道生理学或 趋化因子“敲除”（KO）对发育过程中白细胞群的影响 4）确定特异性抗体的功能， CCR 2和CCR 3 KO小鼠中的趋化因子受体，以及5）为了阐明CCR 2和CCR 3 KO小鼠中的趋化因子受体， 单核细胞趋化蛋白-1和eotaxin对特定白细胞群的激活作用 参与了过敏性气道反应。这些想法的发展 将允许阐明特定介质的机械活性 参与蟑螂过敏原不同阶段的细胞群 气道炎症加重，导致气道高反应性 并帮助确定过敏性疾病 气道。

Despite a substantial increase in our understanding of the mechanism involved in the pathology of asthma, the mortality and morbidity rates continue to rise, especially in inner-city children. The etiology of many inner city asthmatics appears to be related to cockroach-delivered allergens. In the present proposal, we have detailed studies to assess specific mechanisms of a murine model of cockroach allergen-induced airway hyperreactivity which resemble atopic human asthmatics responses. The allergic responses in this model include significant increases in allergen-specific serum IgE, immediate release of histamine in the BAL, allergen-specific airway eosinophilia, and significantly altered airway physiology which correlates to the airway inflammation. The specific focus of the studies in this proposal will examine the mechanisms by which specific chemokines induce airway hyperreactivity at different stages of the cockroach allergen-induced responses. Differential responses at certain stages of allergic airway disease appears to center around the intensity of inflammation at the time of allergen rechallenge and the specific chemokine-mediated activation of local leukocyte populations. We hypothesize that specific CC chemokines which utilize specific receptors will be responsible for inducing airway hyperreactivity at different stages of cockroach allergen-induced airway responses. To test this postulate, the studies outlined in this proposal will examine two CC family chemokines, MCP-1 and eotaxin, which specifically bind to CCR2 and CCR3, respectively, and appear to mediate different responses leading to airway hyperreactivity. Our studies will include the following: 1) To characterize the inflammatory response and chemokine expression profiles at different stages of allergic response, 2) To examine the alteration of inflammation and airway physiology after depletion of the chemokines or in chemokine "knockout" (KO) on leukocyte populations during the development of allergic airway disease, 4) To determine the function of specific chemokine receptors in CCR2 and CCR3 KO mice, and 5) To elucidate the activational role of MCP-1 and eotaxin on specific leukocyte populations involved in the allergic airway responses. The development of these ideas will allow elucidation of the mechanistic activity of specific mediators and cell populations involved at different stages of cockroach allergen exacerbations of airway inflammation, leading to airway hyperreactivity and help define differences in disease progression within the allergic airway.