Role of Acidic Environment in Eosinophilic Inflammation

描述（申请人提供）：嗜酸性粒细胞是健康人体内罕见的白细胞；然而，它们在一系列疾病中大量积累，包括过敏性疾病和哮喘、寄生虫感染和癌症。嗜酸性粒细胞在许多这些疾病中具有致病作用。我们的长期目标是了解嗜酸性粒细胞的机制，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生存能力上。值得注意的是，我们已经证明嗜酸性粒细胞通过改变活力/细胞死亡途径来响应酸性pH。重要的是，哮喘患者过敏性气道微环境是酸性的。在这项拨款申请中，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，建立和验证测量过敏原挑战小鼠气道pH值的新方法至关重要，因为小鼠模型将为研究气道pH值在嗜酸性粒细胞炎症中的作用提供重要的机制研究，建立因果关系和治疗证明原则。本应用的中心假设是气道pH值在嗜酸性气道炎症的病理生理中起作用。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以TDAG8依赖的方式导致嗜酸性粒细胞中cAMP积累增加。在第一个目标中，我们将验证酸性pH抑制嗜酸性粒细胞凋亡的假设，这是由TDAG8和cAMP介导的。先前的研究表明，哮喘患者发作时气道pH值呈酸性。然而，在过敏原挑战小鼠中没有进行类似的测量。此外，调节气道pH值对变应性气道炎症结局的影响尚未确定。因此，第二个目的将检验过敏性气道炎症环境为酸性并影响支气管肺泡间隙嗜酸性粒细胞存活的假设。当我们关注pH值对嗜酸性粒细胞的影响时，过敏性气道炎症中气道pH值测量方法的发展将使未来的研究旨在确定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。本应用的实验将剖析质子在嗜酸性粒细胞中介导效应的关键特性。希望我们的研究将为未来针对嗜酸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：虽然嗜酸性粒细胞在健康个体中是一种罕见的白细胞，但它们在一系列嗜酸性粒细胞介导的疾病（包括哮喘）中大量积累，导致显著的发病率和死亡率。这项拨款申请将研究哮喘患者气道中存在的酸性环境对嗜酸性粒细胞活力和功能以及最终疾病结局的作用。

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.