Asthma Exacerbations: physiology, upper airway & fibrin

描述（由申请人提供）： 哮喘急性发作与生活质量差、死亡风险高相关，并导致哮喘护理费用不成比例。初步证据表明，气道内的许多特定机制和部位可能在哮喘急性发作的发病机制中发挥关键作用。我们将重点关注上呼吸道（鼻和鼻窦）和下呼吸道疾病之间的相关性，以及纤维蛋白对肺功能产生不利影响的能力。我们假设哮喘的加重反映了整个气道树的协调功能障碍，特别是上和大的传导气道，作为嗜酸性粒细胞炎症和纤维蛋白形成的结果。该提案的总体目标是探索哮喘急性发作背后的特定候选机制，并确定这些机制协同作用产生比其部分总和更严重的疾病的程度。我们提出了三个具体目标：具体目标1：确定中央气道对急性哮喘加重的贡献和解决方案;具体目标2：确定嗜酸性粒细胞炎症与上下气道狭窄之间的定量和时间关系;具体目标3：确定下气道内的血管外纤维蛋白如何影响哮喘加重的严重程度。这些目的将在一项综合全面的研究中进行阐述，研究中使用了在急诊室就诊的哮喘急性加重受试者、哮喘稳定受试者和正常对照受试者的病例对照组。我们将利用我们研究者的互补专业知识、我们招募哮喘受试者进行临床研究的既定记录以及两个参与机构的病理生理表型资源。这项研究有望阐明气道炎症和纤维蛋白形成所起的作用，这将加强我们目前对哮喘急性发作发病机制的认识。这些信息可能最终导致新的治疗策略。 (End摘要）

DESCRIPTION (provided by applicant): Exacerbations of asthma are associated with a poor quality of life, a high risk of mortality, and account for a disproportionate cost of asthma care. Preliminary evidence points to a number of specific mechanisms and sites within the air passages that may play critical roles in the pathogenesis of asthma exacerbations. We will focus on the demonstrated associations between disease in the upper (nose & sinuses) and lower airways, and on the ability of fibrin to adversely effect lung function. We hypothesize that exacerbations of asthma reflect a coordinated dysfunction throughout the airway tree, particularly of the upper and large conducting airways, as a consequence of eosinophilic inflammation and fibrin formation. The overall goal of the proposal is to explore specific candidate mechanisms behind an asthma exacerbation, and to establish the extent to which those mechanisms act synergistically to produce a disease that is much worse than the sum of its parts. We propose three specific aims: Specific Aim 1: To determine the contribution and resolution of the central airways to an acute asthma exacerbation; Specific Aim 2: To determine the quantitative and temporal relationships between eosinophilic inflammation and narrowing of the upper and lower airways; Specific Aim 3: To determine how extra-vascular fibrin within the lower airways contributes to the severity of asthma exacerbations. These aims will be addressed in an integrated and comprehensive investigation using case-controlled groups of subjects presenting in the emergency department with acute asthma exacerbations, subjects with stable asthma, and normal controls. We will draw on the complementary expertise of our investigators, our established record of recruiting asthmatic subjects for clinical investigation, and the pathophysiological phenotyping resources at both participating institutions. This research is expected to elucidate the roles played by inflammation and fibrin formation in the airways, which will enhance our current poor understanding of the pathogenesis of asthma exacerbations. Such information may ultimately lead to new therapeutic strategies. (End of Abstract)