Asthma Exacerbations: physiology, upper airway & fibrin

描述(由申请人提供)： 哮喘的恶化与生活质量差、死亡风险高有关，并且占哮喘护理费用的不成比例。初步证据表明，呼吸道内的一些特定机制和部位可能在哮喘恶化的发病机制中发挥关键作用。我们将集中讨论上呼吸道(鼻腔和鼻窦)和下呼吸道疾病之间已证实的联系，以及纤维蛋白对肺功能产生不利影响的能力。我们假设，哮喘的恶化反映了整个气道树的协调功能障碍，特别是由于嗜酸性炎症和纤维蛋白的形成，尤其是上部和大型传导气道的功能障碍。该提案的总体目标是探索哮喘恶化背后的特定候选机制，并确定这些机制在多大程度上协同作用，产生一种比其各部分之和严重得多的疾病。我们提出了三个具体目标：具体目标1：确定中央气道对哮喘急性加重的贡献和解决；具体目标2：确定嗜酸性炎症与上下呼吸道狭窄之间的定量和时间关系；具体目标3：确定下呼吸道血管外纤维蛋白如何促进哮喘加重。这些目标将在一项综合和全面的调查中得到解决，研究对象包括急诊科出现的急性哮喘加重患者组、哮喘稳定患者组和正常对照组。我们将利用我们研究人员的互补专业知识、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。这项研究有望阐明炎症和纤维蛋白形成在呼吸道中所起的作用，这将加强我们目前对哮喘恶化发病机制的了解。这些信息最终可能导致新的治疗策略。(摘要结束)

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)