Mechanisms of airways pH deviation in asthma and chronic cough

描述(由申请人提供)： 弗吉尼亚大学的研究项目专注于调查哮喘的病因，既关注疾病的风险因素，也关注围绕急性发作的复杂事件。这些研究提供了大量证据，证明了长期暴露于室内过敏原的影响，以及病毒与医院急性发作的相关性；慢性鼻窦疾病的作用；以及最近肺部衬里液体中pH值变化的影响。此外，这些研究还探讨了T细胞在变态反应性疾病中作为效应细胞和调节细胞发挥作用的机制。本提案的四个项目是作为单独和不同的研究计划提出的，但它们已经形成，并将继续涉及多个层面的强有力的互动。项目1：高危人群中与哮喘相关的过敏原暴露、IgE反应和总IgE：这些研究将调查：a)家庭暴露、致敏和炎症反应之间的相互作用；b)农村和城市学校青少年儿童的肺部症状和哮喘，重点关注身体健康、肥胖和代谢综合征以及过敏反应和炎症之间的相互作用。项目2：人类中的CD25+CD4+T细胞和IgE介导的疾病：将分析与IgE反应相关的新的CD25+CD4+亚群的表型和功能。研究将包括通过监测特应性皮炎儿童出生后几年的循环T细胞，以及检查抗LGE治疗对哮喘受试者离散T细胞亚群的影响，来研究这些细胞与IgE之间的联系。项目3：慢性增生性嗜酸性鼻窦炎对哮喘的影响：研究将调查鼻窦组织通过TH2样淋巴细胞、嗜酸性粒细胞、嗜碱性粒细胞和纤维细胞的产生和再循环而促进全身炎症反应的假设；这些细胞反过来影响鼻窦相关淋巴组织、骨髓和肺。项目4：哮喘和慢性咳嗽中pH偏离的机制：使用测量呼气pH的新方法，研究将重点区分原发呼吸道酸化和胃酸吸入的患者。这些研究将探讨与慢性咳嗽或急性哮喘恶化的呼吸道酸化相关的细胞和生化病理学。 项目1：高危人群中与哮喘相关的过敏原暴露、IgE反应和总IgE(Pi Platts-Mills，T.) 项目1描述(申请人提供)： 在20世纪的最后40年里，哮喘已经在西方世界的大部分地区流行起来。特别是，哮喘已成为美国城市贫困人口旷课、住院和死亡的重要原因。虽然许多变化被认为是造成这一增长的原因，但时间进程(即1960-2000年)的真正原因尚不清楚。然而，很明显，大多数因哮喘住院的非裔美国儿童和成年人对一种或多种室内过敏原过敏，特别是来自尘螨或蟑螂的过敏原。在这段时间里，生活方式发生了重大变化，导致户外活动时间减少，久坐时间增加，肥胖率上升。为了进一步了解导致哮喘的不同因素之间的相互作用，将采用几种不同的方法。第一项将使用新技术来测量家庭中的过敏原和内毒素暴露，以及一种新的方法来测量空气中颗粒物的特异性IgE抗体。本研究的目的是探讨贫困人群过敏原暴露与免疫应答之间的剂量效应关系。第二个目标是评估急诊科哮喘患者中IgE抗体应答与炎症之间的关系。这些患者始终--70%没有保险，50%来自少数群体。在这项研究中，将使用嗜酸性粒细胞增多症、呼出的一氧化氮(ENO)和鼻窦CT评分等“传统”标记物以及血清细胞因子和尿液白三烯的测量来研究与哮喘相关的炎症。最后，将对14-16岁的青少年进行研究，以确定体育活动、肥胖和过敏性致敏对哮喘症状和呼吸道炎症的独立影响。参与者将完成一项带有肺功能的锻炼方案，并将接受炎症和过敏性过敏证据的评估。目的是回答肥胖、体能下降或代谢综合征是否会影响哮喘的症状或生理效应。正如在特定目标2中一样，炎症将通过传统标记物以及细胞因子和白三烯的测定来评估。这些研究将适用于农村和城市的学龄儿童。总体目标是了解肥胖、体力活动和过敏性敏化对呼吸困难和呼吸道阻塞症状的影响。

DESCRIPTION (provided by applicant): The research program of the University of Virginia has focused on investigating the etiology of asthma, looking both at risk factors for the disease and the complex events surrounding an acute episode. These studies have provided extensive evidence about effects of chronic exposure to indoor allergens, as well as the relevance of viruses to acute episodes in the hospital; the role of chronic sinus disease; and most recently the effects of pH changes in the lung lining fluid. In addition, the studies have addressed the mechanisms by which T cells contribute as effector cells and regulatory cells in allergic disease. The four projects of the current proposal are presented as separate and distinct research plans, but they have developed from, and will continue to involve, strong interactions at multiple levels. Project 1: Allergen exposure, IgE responses, and total IgE in relation to asthma in at risk populations: The studies will investigate: a) the interaction between home exposure, sensitization, and inflammatory responses among adult patients presenting with acute asthma; b) lung symptoms and asthma among teenage children in rural and city schools, focusing on the interaction between physical fitness, obesity, and metabolic syndrome on the one hand, and allergic responses and inflammation on the other. Project 2: CD25+CD4+ T cells and IgE-mediated disease in humans: The phenotype and function of a novel CD25+CD4+ subset associated with IgE responses will be analyzed. Studies will include investigation of the link between these cells and IgE by monitoring circulating T cells in children with atopic dermatitis during the first years of life, and examining the effects of anti-lgE therapy on discrete T cell subsets in asthmatic subjects. Project 3: Impact of chronic hyperplastic eosinophilic sinusitis on asthma: Studies will investigate the hypothesis that the sinus tissue contributes to the systemic inflammatory response through the production of, and recirculation of, TH2-like lymphocytes, eosinophils, basophils, and fibrocytes; and that those cells in turn influence sinus associated lymphatic tissue, bone marrow, and the lungs. Project 4: Mechanisms of pH deviation in asthma and chronic cough: Using new methods of measuring exhaled breath pH, the studies will focus on distinguishing between patients with primary airway acidification and gastric acid aspiration. The studies will address cellular and biochemical pathology related to airway acidification in the setting of chronic cough or acute asthma exacerbations. PROJECT 1: Allergen Exposure, IgE Responses, and Total IgE in Relation to Asthma in at Risk Populations (PI Platts-Mills, T.) PROJECT 1 DESCRIPTION (provided by applicant): Over the last 40 years of the 20th century asthma has become epidemic in most of the Western World. In particular asthma has become an important cause of school absenteeism, hospitalization and mortality among populations living in poverty in the cities of the United States. Although many changes are thought to have contributed to the increase the real reasons for the time course (i.e. 1960-2000) are not clear. However it is clear that the majority of African American children and adults admitted to hospital with asthma are allergic to one or more indoor allergens, particularly those from dust mite or cockroach. Over this same time period there have been major changes in lifestyle leading to decreased time outdoors, more time sedentary and a rise in obesity. To further understand the interaction between different factors contributing to asthma, several different approaches will be employed. The first will use new techniques to measure allergen and endotoxin exposure in homes, and a novel approach to measuring IgE antibodies specific for airborne particles. The objective is to investigate the dose response relationship between exposure and immune responses to allergens for patients living in poverty. The second aim is to assess the relationships between IgE ab response and inflammation among the patients presenting to an emergency department with asthma. These patients are consistently -70% uninsured and 50% from a minority group. In this study the inflammation associated with asthma will be studied using both "traditional" markers such as eosinophilia, exhaled NO (eNO) and sinus CT score; as well as measurements of cytokines in serum and leukotrienes in urine. Finally teenagers aged 14-16 years will be studied to determine the independent effects of physical activity, obesity and allergic sensitization on asthmatic symptoms and airway inflammation. The participants will complete an exercise protocol with lung function and will be assessed for evidence of inflammation and allergic sensitization. The objective is to answer whether obesity, decreased fitness, or the metabolic syndrome influence the symptoms or the physiological effects of asthma. As in specific aim 2, inflammation will be assessed both by traditional markers and by assay of cytokines and leukotrienes. These studies will be applied to both rural and city school age children. The overall objective is to understand the effects of obesity, physical activity and allergic sensitization in relation to symptoms of breathlessness and airway obstruction.