Asthma, Airway Inflammation and Beta Chemokine Receptors

描述（由申请人提供）：在过去十年中，在阐明气道炎症性疾病的病理生理机制方面取得了很大进展。然而，关于趋化因子及其受体在协调病理学中的具体作用仍存在相当大的争议。在这项资助的最后一个资助周期中，我们专注于两种β趋化因子受体CCR 1和CCR 3，通过使用基因缺失的小鼠，在几种特征良好的肺部疾病模型中研究它们的作用。此外，我们的特点嗜酸性粒细胞谱系消融小鼠（？dblGATA）。我们的数据支持CCR 3结扎作为嗜酸性粒细胞募集的主要机制，在基线以及对损伤或感染的反应中。利用？dblGATA小鼠，我们证明了过敏性气道高反应性发生在嗜酸性粒细胞的情况下，但这些细胞可以控制气道重塑的功能。在本更新申请的具体目标1中，我们提出了实验来确定CCR 3-/-小鼠是否类似地免受过敏性气道重塑。在初步研究中，我们发现了CCR 1在RSV感染的病理生理学中的潜在作用，尽管过敏反应的叠加揭示了其复杂性。在我们关注气道高反应性和嗜酸性粒细胞的作用时，新收集到的这种细胞类型作用的变异性似乎来自于给药方式和过敏原性质的微妙之处，以及背景小鼠遗传学。由于小鼠（和人）在缺乏适应性免疫反应的情况下对RSV产生气道高反应性，因此我们选择研究气道损伤的这种机制。我们假设Fractalkine/CX 3CR 1轴在RSV肺病中的重要作用，并将定义RSV G糖蛋白破坏先天免疫应答的机制。这些研究的成功完成将为RSV诱导的肺损伤的病理生理学提供额外的机制理解以及药物开发的临床前验证。公共卫生相关性：由于小鼠（和人）在缺乏适应性免疫反应的情况下对RSV产生气道高反应性，因此我们选择研究气道损伤的这种机制。我们假设Fractalkine/CX 3CR 1轴在RSV肺病中的重要作用，并将定义RSV G糖蛋白破坏先天免疫应答的机制。这些研究的成功完成将为RSV诱导的肺损伤的病理生理学提供额外的机制理解以及药物开发的临床前验证。

DESCRIPTION (provided by applicant): Great progress has been made over the past decade in elucidating pathophysiologic mechanisms in airways inflammatory diseases. Considerable controversy remains however, relating to the specific role of chemokines and their receptors in orchestrating the pathology. During the last funding cycle of this grant, we focused on two beta chemokine receptors, CCR1 and CCR3, examining their role, through the use of mice with genetic deletions, in several well-characterized models of lung disease. We additionally characterized eosinophil lineage ablated mice (?dblGATA) in both acute and chronic models of allergic airway inflammation. Our data support CCR3 ligation as the dominant mechanism for eosinophil recruitment, at baseline as well as in response to injury or infection. Using the ?dblGATA mice, we demonstrated that allergic airway hyperresponsiveness occurs in the absence of eosinophils, but that these cells may control features of airway remodeling. In Specific Aim 1 of this renewal application, we propose experiments to determine whether CCR3-/- mice are similarly protected from allergic airway remodeling. In preliminary studies we find a potential role for CCR1 in the pathophysiology of RSV infection, although complexities are revealed by superimposition of an allergic reaction. In our focus on airway hyperresponsiveness and the role of eosinophils, the newly gleaned variability in the role of this cell type appears to derive from subtleties in the mode of administration and nature of the allergen, as well as background mouse genetics. Since mice (and humans) develop airway hyperresponsiveness to RSV in the absence of an adaptive immune reaction, we have opted to investigate this mechanism of airway injury. We hypothesize a significant role for the fractalkine/CX3CR1 axis in RSV lung disease and will define the mechanism by which the RSV G glycoprotein subverts innate immune responses. Successful completion of these studies will provide additional mechanistic understanding of the pathophysiology of RSV induced lung injury as well as preclinical validation for drug development. PUBLIC HEALTH RELEVANCE: Since mice (and humans) develop airway hyperresponsiveness to RSV in the absence of an adaptive immune reaction, we have opted to investigate this mechanism of airway injury. We hypothesize a significant role for the fractalkine/CX3CR1 axis in RSV lung disease and will define the mechanism by which the RSV G glycoprotein subverts innate immune responses. Successful completion of these studies will provide additional mechanistic understanding of the pathophysiology of RSV induced lung injury as well as preclinical validation for drug development.