Role of Acidic Environment in Eosinophilic Inflammation

描述(申请人提供)：嗜酸性粒细胞是健康个体中罕见的白细胞；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。嗜酸性粒细胞在这些疾病中的致病作用已被证实。我们的长期目标是了解嗜酸性粒细胞增多症的机制，最终目的是改变嗜酸性粒细胞介导的疾病的结局。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存活/细胞死亡途径来对酸性pH作出反应。重要的是，哮喘患者过敏性呼吸道的微环境是酸性的。在这项拨款申请中，我们建议将重点放在过敏性呼吸道炎症的小鼠模型上，在这些模型中，呼吸道的pH值尚未被测量。我们认为，建立和验证新的方法来测量过敏原挑战小鼠的呼吸道pH值是至关重要的，因为小鼠模型将为研究气道pH值在嗜酸性炎症中的作用提供重要的机制研究、因果关系和治疗原则证明。这一应用的中心假设是，气道pH在嗜酸性气道炎的病理生理学中起作用。我们的初步数据表明，酸性pH会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内cAMP积累增加。在第一个目标中，我们将检验酸性pH抑制嗜酸性粒细胞凋亡的假设，即这是通过TDAG8和cAMP介导的。以往的研究表明，在哮喘患者的急性发作期间，呼吸道的pH值是酸性的。然而，类似的测量还没有在过敏原挑战的小鼠身上进行。此外，调节呼吸道pH值对过敏性呼吸道炎症结局的影响尚未确定。因此，第二个目标将检验过敏性呼吸道炎症环境是酸性的，并影响嗜酸性粒细胞在支气管肺泡腔的存活的假设。虽然我们关注的是pH对嗜酸性粒细胞的影响，但在过敏性气道炎中测量气道pH的方法的发展将使未来的研究旨在确定pH对其他哮喘相关表型的影响，如纤毛搏动、粘液粘度、咳嗽反射和支气管收缩。这一应用中的实验将剖析嗜酸性粒细胞中质子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和哮喘的翻译和临床研究提供重要的初步数据。公共卫生相关性：虽然嗜酸性粒细胞是健康个体中一种罕见的白细胞类型，但它们在包括哮喘在内的一系列嗜酸性粒细胞介导的疾病中大量积累，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呼吸道中存在的酸性环境对嗜酸性粒细胞活性和功能的作用，并最终导致疾病结局。

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.