Asthma, Airway Inflammation and Beta Chemokine Receptors

在过去的十年里，在阐明糖尿病的病理生理机制方面取得了很大的进展。 航空公司炎症性疾病。然而，与具体的 趋化因子及其受体在病理过程中的作用。在上一个资金周期中 在这项资助中，我们专注于两个β趋化因子受体，CCR1和CCR3，研究它们的作用， 通过使用带有基因缺失的小鼠，在几种具有良好特征的肺部疾病模型中。 此外，我们还鉴定了急性和慢性嗜酸性粒细胞系去化小鼠(DblGATA)的特征 过敏性呼吸道炎症模型。我们的数据支持CCR3连接是主要机制 对于嗜酸性粒细胞招募，在基线以及对伤害或感染的反应中。使用 DblGATA小鼠，我们证明了过敏性呼吸道高反应性发生在缺乏 嗜酸性粒细胞，但这些细胞可能控制着呼吸道重塑的特征。在此的具体目标1中 更新应用，我们提出实验来确定CCR3-/-小鼠是否类似 防止过敏性呼吸道重塑。在初步研究中，我们发现了CCR1的潜在作用 在RSV感染的病理生理学中，尽管复杂性是通过重叠的 过敏反应。 在我们关注呼吸道高反应性和嗜酸性粒细胞的作用时，新收集的 这种细胞类型的作用的可变性似乎源于给药模式的微妙之处 过敏原的性质，以及背景老鼠的遗传学。因为老鼠(和人类) 呼吸道对RSV的高反应性在没有适应性免疫反应的情况下，我们选择了 目的：探讨呼吸道损伤的发病机制。我们假设一个重要的角色 Fractalkine/CX3CR1轴在呼吸道合胞病毒肺部疾病中的作用，并将定义呼吸道合胞病毒 G糖蛋白可以破坏先天免疫反应。成功完成这些研究将 对呼吸道合胞病毒引起的肺损伤的病理生理机制有更多的了解 以及药物开发的临床前验证。

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.