Immunopathology of Indirect Airway Hyperresponsiveness in Asthma

K24：哮喘间接气道高反应性的免疫病理学 项目摘要 间接或内源性的呼吸道高反应性(AHR)是哮喘的一个基本特征，而不是 完全理解。与哮喘的其他特征，如气流阻塞或对 外源性支气管收缩因子如乙酰胆碱、内源性AHR专用于哮喘并可复制 引起哮喘的许多常见诱因包括对冷/干空气的反应、高渗气溶胶和 适当致敏的个体中的过敏原。我们把重点放在了运动引起的 支气管收缩(EIB)是内源性AHR的典型特征，因为它是 症状与哮喘进展的风险有关，不需要过敏性致敏和 可以在实验室中精确测量。我们实验室最近的研究显示，在精确的 肥大细胞在从粘膜下层到上皮的呼吸道中的定位以及肥大细胞和嗜酸性粒细胞的分布 (Eos)与呼吸道上皮细胞相互作用，从而促进呼吸道炎症。我们有 还发现了磷脂代谢和一种称为分泌型磷脂酶A2的特殊酶的变化 第10组(sPLA2-X)，与AHR密切相关，并与调节失调的脂质介质有关 哮喘的呼吸道中存在新陈代谢。我的研究计划的总体目标是了解 导致人类内源性AHR的呼吸道潜在变化。我们假设MC 和Eos与上皮细胞协同作用促进呼吸道炎症和磷脂的改变 新陈代谢通过产生介质来激活感觉神经，从而发挥关键作用。在 首先，我们确定了呼吸道MC祖细胞数量和增殖能力的差异。 并利用体外模型研究MCs、Eos和呼吸道上皮细胞(AEC)之间的相互作用。 用来传播呼吸道炎症。在第二个目的中，我们研究了sPLA2-X在先天性中的功能 免疫细胞，并探索该酶的细胞外抑制物在大鼠模型中的治疗潜力 欧洲投资银行。在最终目标中，我们使用基于设计的体视学来检查细胞和结构的精确位置 并将该信息与对呼吸道上皮刷毛的转录分析相结合，以 确定AHR在哮喘中的基础。这些项目通过更好的方式推动该领域向前发展 了解哮喘AHR的基础，并将支持下一代的职业发展 以病人为中心的研究人员对哮喘的免疫病理学感兴趣。

K24: Immunopathology of Indirect Airway Hyperresponsiveness in Asthma Project Summary Indirect or "endogenous" airway hyperresponsiveness (AHR) is a fundamental feature of asthma that is not fully understood. In contrast to other features of asthma such as airflow obstruction or the response to an exogenous bronchoconstrictor such as methacholine, endogenous AHR is specific for asthma and replicates many of the common triggers for asthma including the response to cold/dry air, hypertonic aerosols and allergens in individuals who are appropriately sensitized. We have focused on exercise-induced bronchoconstriction (EIB) as a prototypical feature of endogenous AHR because it is a common trigger for symptoms, has been associated with risk of asthma progression, does not require allergic sensitization and can be precisely measured in the laboratory. Recent studies from our lab have revealed a shift in the precise location of mast cells (MCs) in the airways from the submucosa to the epithelium and that MCs and eosinophils (Eos) interact with the airway epithelium in a manner that serves to propagate airway inflammation. We have also identified alterations in phospholipid metabolism and a specific enzyme called secreted phospholipase A2 group 10 (sPLA2-X) that is strongly associated with AHR and contributes to the dysregulated lipid mediator metabolism present in asthmatic airways. The overall goal of my research program is to understand the underlying alterations in the airways that lead to endogenous AHR in humans. We hypothesize that MCs and Eos act in concert with the epithelium to promote airway inflammation and that alterations in phospholipid metabolism play a key role through generation of mediators that serve to activate the sensory nerves. In the first aim, we determine differences in the number and proliferation potential of MC progenitors in the airways and utilize ex vivo models to examine how interactions among MCs, Eos and airway epithelial cells (AECs) serve to propagate airway inflammation. In the second aim, we examine the function of sPLA2-X in innate immune cells and explore the therapeutic potential of an extracellular inhibitor of this enzyme in a model of EIB. In the final aim, we use design-based stereology to examine the precise location of cells and structures in the airway wall and integrate this information with transcriptomic analyses of airway epithelial brushings to identify the underpinnings of AHR in asthma. These projects move the field forward through a better understanding of the basis for AHR in asthma and will support the career development of the next generation of patient-oriented researchers interested in the immunopathology of asthma.