Role of Acidic Environment in Eosinophilic Inflammation

描述（由申请人提供）：嗜酸性粒细胞是健康个体中罕见的白色血细胞;然而，它们在过敏性疾病和哮喘、寄生虫感染和癌症等一系列疾病中大量蓄积。嗜酸性粒细胞的致病作用已被确定在许多这些疾病。我们的长期目标是了解嗜酸性粒细胞增多的机制，最终目的是改变嗜酸性粒细胞介导的疾病的结果。我们最近的研究集中在嗜酸性粒细胞的活力。值得注意的是，我们已经证明，嗜酸性粒细胞响应酸性pH值的活力/细胞死亡途径的改变。重要的是，哮喘患者过敏性气道的微环境是酸性的。在这项资助申请中，我们建议将重点放在过敏性气道炎症的小鼠模型上，其中气道pH值尚未测量。我们认为，建立和验证新方法至关重要，该方法将测量过敏原激发小鼠的气道pH值，因为小鼠模型将能够进行重要的机制研究，建立因果关系和治疗原理验证，以研究气道pH值在嗜酸性粒细胞炎症中的作用。本申请的中心假设是气道pH在嗜酸性粒细胞气道炎症的病理生理学中起作用。我们的初步数据表明，酸性pH值影响嗜酸性粒细胞的活力。我们的初步数据还表明，酸性pH值导致增加cAMP的积累在嗜酸性粒细胞中的TDAG 8依赖性的方式。在第一个目标中，我们将测试酸性pH抑制嗜酸性粒细胞凋亡的假设，这是由TDAG 8和cAMP介导的。先前的研究表明，在哮喘患者的急性发作期间，气道pH呈酸性。然而，在过敏原激发的小鼠中尚未进行类似的测量。此外，调节气道pH值对过敏性气道炎症结果的影响尚未确定。因此，第二个目标将测试过敏性气道炎症的环境是酸性的，并影响支气管肺泡腔内嗜酸性粒细胞的存活的假设。虽然我们专注于pH值对嗜酸性粒细胞的影响，但过敏性气道炎症气道pH值测量方法的发展将使未来的研究能够确定pH值对其他哮喘相关表型的影响，如纤毛跳动，粘液粘度，咳嗽反射和支气管收缩。在这个应用程序中的实验将解剖质子介导的嗜酸性粒细胞的影响的关键属性。希望我们的研究能为将来嗜酸性粒细胞性气道炎症和哮喘的转化和临床研究提供关键的初步数据。公共卫生相关性：虽然嗜酸性粒细胞是健康个体中罕见的白色血细胞类型，但它们在嗜酸性粒细胞介导的疾病谱（包括哮喘）中大量积聚，导致显著的发病率和死亡率。这项拨款申请将研究酸性环境的作用，这是目前在气道的哮喘患者，对嗜酸性粒细胞的活力和功能，并最终疾病的结果。

DESCRIPTION (provided by applicant): Eosinophils are rare white blood cells in healthy individuals; however, they accumulate in larger numbers in a spectrum of disorders ranging from allergic diseases and asthma, parasitic infections, and cancer. A pathogenic role for eosinophils has been established in many of these disorders. Our long-term goal is to understand the mechanisms of eosinophilia with the ultimate aim of changing the outcome of eosinophil-mediated diseases. Our recent studies have focused on eosinophil viability. Notably, we have demonstrated that eosinophils respond to acidic pH by alterations in viability/cell death pathway. Importantly, the microenvironment of allergic airway in patients with asthma is acidic. In this grant application we propose to focus on mouse models of allergic airway inflammation, in which airway pH has not been measured. We believe it is critical to establish and validate novel methods that will measure the airway pH in allergen-challenged mice, as mouse models will enable important mechanistic studies, establishment of causality and therapeutic proof-of- principle for studies in the role of airway pH in eosinophilic inflammation. The central hypothesis of this application is that airway pH has a role in pathophysiology of eosinophilic airway inflammation. Our preliminary data suggest that acidic pH affects eosinophil viability. Our preliminary data also demonstrates that acidic pH leads to increased cAMP accumulation in eosinophils in a TDAG8- dependent manner. In the first aim, we will test the hypothesis that acidic pH inhibits eosinophil apoptosis and that this is mediated by TDAG8 and cAMP. Previous studies have shown that airway pH is acidic during exacerbations of asthma in patients. However, similar measurements have not been performed in allergen-challenged mice. Furthermore, the effect of modulating airway pH on outcomes of allergic airway inflammation has not been determined. Thus, the second aim will test the hypothesis that the milieu of allergic airway inflammation is acidic and affects survival of eosinophils in the bronchoalveolar space. While we focus on the effect of pH on eosinophils, development of methods for measurement of airway pH in allergic airway inflammation will enable future studies aimed at determining the effect of pH on other asthma-related phenotypes, such as ciliary beating, mucus viscosity, cough reflex, and bronchoconstriction. Experiments in this application will dissect critical properties of proton-mediated effects in eosinophils. It is hoped that our studies will provide critical preliminary data for future translational and clinical studies aimed at eosinophilic airway inflammation and asthma. PUBLIC HEALTH RELEVANCE: While eosinophils are a rare type of white blood cells in healthy individuals, they accumulate in large numbers in a spectrum of eosinophil-mediated diseases, including asthma, leading to significant morbidity and mortality. This grant application will research the role of acidic environment, that is present in the airways of patients with asthma, on eosinophil viability and function, and ultimately disease outcomes.