Asthma, Airway Inflammation and Beta Chemokine Receptors

描述（申请人提供）：在过去的十年中，在阐明气道炎症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中的具体作用，仍存在相当大的争议。在该基金的最后一个资助周期中，我们专注于两种β趋化因子受体CCR1和CCR3，通过使用具有遗传缺失的小鼠，研究它们在几种具有良好特征的肺部疾病模型中的作用。我们还研究了嗜酸性粒细胞系消融小鼠(？dblGATA)在急性和慢性模型过敏性气道炎症中的作用。我们的数据支持CCR3连接是嗜酸性粒细胞招募的主要机制，无论是在基线还是在对损伤或感染的反应中。使用？在dblGATA小鼠中，我们证明了过敏性气道高反应性发生在缺乏嗜酸性粒细胞的情况下，但这些细胞可能控制气道重塑的特征。在这项更新申请的Specific Aim 1中，我们提出了实验来确定CCR3-/-小鼠是否同样受到过敏性气道重塑的保护。在初步研究中，我们发现CCR1在RSV感染病理生理中的潜在作用，尽管其复杂性是通过叠加过敏反应揭示的。在我们对气道高反应性和嗜酸性粒细胞作用的关注中，新收集到的这种细胞类型的作用变异性似乎源于过敏原给药模式和性质的微妙之处，以及小鼠遗传背景。由于小鼠（和人类）在没有适应性免疫反应的情况下对RSV产生气道高反应性，我们选择研究这种气道损伤机制。我们假设fractalkine/CX3CR1轴在RSV肺部疾病中发挥重要作用，并将确定RSV G糖蛋白破坏先天免疫反应的机制。这些研究的成功完成将为RSV诱导肺损伤的病理生理学提供额外的机制理解，并为药物开发提供临床前验证。公共卫生相关性：由于小鼠（和人类）在没有适应性免疫反应的情况下对RSV产生气道高反应性，我们选择研究这种气道损伤机制。我们假设fractalkine/CX3CR1轴在RSV肺部疾病中发挥重要作用，并将确定RSV G糖蛋白破坏先天免疫反应的机制。这些研究的成功完成将为RSV诱导肺损伤的病理生理学提供额外的机制理解，并为药物开发提供临床前验证。

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.