Immunopathology of Indirect Airway Hyperresponsiveness in Asthma

哮喘间接气道高反应性的免疫病理学

• 批准号: 10369284
• 负责人: TEAL S HALLSTRAND
• 金额: $ 13.41万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-18 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369284
• 关键词: Abbreviations; Aerosols; Air; Allergens; Allergic; Asthma; Biopsy Specimen; Bronchoconstriction; Bronchoconstrictor Agents; Cell Culture Techniques; Cells; Cellular Structures; Environment; Enzyme Inhibitor Drugs; Enzymes; Epithelial; Epithelial Cells; Exercise; Gene Expression; Generations; Genes; Genomics; Goals; Human; Hyperpnea; Immune; Individual; Infiltration; Inflammation; Laboratories; Lead; Location; Lysophospholipids; MUC5AC gene; Measures; Mediating; Mediator of activation protein; Metabolism; Modeling; Mucins; Names; Nerve; Neurokinin A; Patients; Phenotype; Phospholipase A2; Phospholipid Metabolism; Physiology; Play; Pre-Clinical Model; Research; Research Personnel; Risk; Role; Sampling; Severities; Source; Structure; Submucosa; Substance P; Symptoms; TAC1 gene; Therapeutic; Training Support; afferent nerve; airway epithelium; airway hyperresponsiveness; airway inflammation; airway obstruction; asthmatic; asthmatic airway; base; career development; cytokine; design; eicosanoid metabolism; eosinophil; extracellular; immunopathology; interest; lipid mediator; macrophage; mast cell; methacholine; next generation; patient oriented; peripheral blood; progenitor; programs; respiratory smooth muscle; response; small molecule inhibitor; stem cells; training opportunity; transcriptomics

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.

K24：哮喘间接气道高反应性的免疫病理学 项目概要 间接或“内源性”气道高反应性 (AHR) 是哮喘的一个基本特征，但并非如此。 完全明白了。与哮喘的其他特征（例如气流阻塞或对哮喘的反应）相反 外源性支气管收缩剂如乙酰甲胆碱、内源性 AHR 对哮喘具有特异性并可复制 哮喘的许多常见诱因包括对冷/干燥空气、高渗气溶胶和 适当致敏的个体中的过敏原。我们重点关注运动引起的 支气管收缩（EIB）作为内源性 AHR 的典型特征，因为它是 症状，与哮喘进展的风险相关，不需要过敏致敏，并且 可以在实验室中精确测量。我们实验室最近的研究揭示了精确的转变 肥大细胞 (MC) 在气道中从粘膜下层到上皮的位置以及 MC 和嗜酸性粒细胞 (Eos) 与气道上皮相互作用，从而传播气道炎症。我们有 还发现了磷脂代谢的改变和一种称为分泌型磷脂酶 A2 的特定酶 组 10 (sPLA2-X) 与 AHR 密切相关并导致脂质介质失调 哮喘气道中存在新陈代谢。我的研究计划的总体目标是了解 导致人类内源性 AHR 的气道的潜在改变。我们假设 MC Eos 与上皮细胞协同作用，促进气道炎症和磷脂的改变 新陈代谢通过产生激活感觉神经的介质而发挥关键作用。在 第一个目标是确定气道中 MC 祖细胞的数量和增殖潜力的差异 并利用离体模型来检查 MC、Eos 和气道上皮细胞 (AEC) 之间的相互作用 有助于传播气道炎症。在第二个目标中，我们检查了 sPLA2-X 在先天性中的功能。 免疫细胞，并在免疫细胞模型中探索该酶的细胞外抑制剂的治疗潜力 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。 气道壁并将这些信息与气道上皮刷洗的转录组分析相结合 确定哮喘 AHR 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 对哮喘免疫病理学感兴趣的以患者为中心的研究人员。