Asthma, Airway Inflammation and Beta Chemokine Receptors

描述(由申请人提供)：在过去的十年里，在阐明呼吸道炎症性疾病的病理生理机制方面取得了很大的进展。然而，关于趋化因子及其受体在组织病理中的具体作用，仍然存在相当大的争议。在这笔赠款的上一个资金周期中，我们专注于两个β趋化因子受体CCR1和CCR3，通过使用带有基因缺失的小鼠，检查它们在几种具有良好特征的肺部疾病模型中的作用。此外，我们还在急性和慢性过敏性呼吸道炎症模型中表征了嗜酸性粒细胞系消融小鼠(？dblGATA)的特征。我们的数据支持CCR3结扎是嗜酸性粒细胞招募的主要机制，在基线以及对损伤或感染的反应中。利用dblGATA小鼠，我们证明了在没有嗜酸性粒细胞的情况下，过敏性气道高反应性发生，但这些细胞可能控制着气道重塑的特征。在这一更新应用的具体目标1中，我们提议进行实验，以确定CCR3-/-小鼠是否受到类似的保护，免受过敏性呼吸道重塑的影响。在初步研究中，我们发现CCR1在RSV感染的病理生理学中具有潜在的作用，尽管复杂性是通过叠加过敏反应而揭示的。在我们对呼吸道高反应性和嗜酸性粒细胞的作用的关注中，新收集到的这类细胞角色的可变性似乎源于给药模式和过敏原性质的微妙之处，以及背景鼠的遗传学。由于小鼠(和人类)在没有适应性免疫反应的情况下对呼吸道合胞病毒产生高反应性，我们选择了研究这种呼吸道损伤的机制。我们假设Fractalkine/CX3CR1轴在RSV肺部疾病中起重要作用，并将确定RSV G糖蛋白颠覆先天免疫反应的机制。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更多的机制理解，并为药物开发提供临床前的验证。公共卫生相关性：由于小鼠(和人类)在缺乏适应性免疫反应的情况下对呼吸道合胞病毒产生高反应性，我们选择了研究这种呼吸道损伤的机制。我们假设Fractalkine/CX3CR1轴在RSV肺部疾病中起重要作用，并将确定RSV G糖蛋白颠覆先天免疫反应的机制。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更多的机制理解，并为药物开发提供临床前的验证。

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.