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: 10661502
• 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/10661502
• 关键词: Abbreviations; Aerosols; Air; Allergens; Allergic; Asthma; Biopsy Specimen; Bronchoconstriction; Bronchoconstrictor Agents; Cell Culture Techniques; Cell secretion; Cells; Dryness; Environment; Enzyme Inhibitor Drugs; Enzymes; Epithelial Cells; Epithelium; Exercise; Gene Expression; Generations; Genes; Genomics; Goals; Human; Hyperpnea; Immune; Individual; Infiltration; Inflammation; Laboratories; Location; Lysophospholipids; MUC5AC gene; Macrophage; Measures; Mediating; Mediator; 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; afferent nerve; airway epithelium; airway hyperresponsiveness; airway inflammation; airway obstruction; asthmatic; asthmatic airway; career development; cytokine; design; eicosanoid metabolism; eosinophil; extracellular; immunopathology; interest; lipid mediator; mast cell; methacholine; next generation; patient oriented; peripheral blood; programs; proliferation potential; 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 项目摘要 间接或“内源性”气道高反应性（AHR）是哮喘的基本特征 完全理解。与其他哮喘的特征（例如气流阻塞或对 外源支气管收缩剂（例如甲基胆碱），内源性AHR特异于哮喘，并重复 许多常见的哮喘触发因素，包括对冷/干空气的反应，高渗气溶胶和 适当敏感的个体中的过敏原。我们专注于锻炼 支气管收缩（EIB）是内源性AHR的典型特征，因为它是常见的触发因素 症状与哮喘进展的风险有关，不需要过敏敏化和 可以精确测量实验室。我们实验室的最新研究表明，精确的转变 肥大细胞（MC）的位置从粘膜下皮到上皮的气道和MCS和嗜酸性粒细胞 （EOS）以传播气道炎症的方式与气道上皮相互作用。我们有 还确定了磷脂代谢的改变和一种称为分泌磷脂酶A2的特异性酶 第10组（SPLA2-X）与AHR密切相关并导致失调的脂质介质 哮喘气道中存在代谢。我的研究计划的总体目标是了解 气道的基本变化导致人类内源性AHR。我们假设MCS EOS与上皮一起起作用，以促进气道炎症和磷脂的改变 代谢通过产生激活感官神经的介体来发挥关键作用。在 第一个目的，我们确定MC祖细胞数量和增殖潜力的差异 并利用离体模型来检查MC，EOS和气道上皮细胞之间的相互作用如何（AEC） 用于传播气道炎症。在第二个目标中，我们检查了spla2-x先天性的功能 免疫细胞并探索该酶的细胞外抑制剂的治疗潜力 EIB。在最终目标中，我们使用基于设计的立体学来检查单元和结构在 气道墙并将这些信息与气道上皮刷子的转录组分析相结合到 确定哮喘中AHR的基础。这些项目通过更好 了解哮喘中AHR的基础，并将支持下一代的职业发展 对患者的研究人员对哮喘的免疫病理感兴趣。

项目成果

Exploring the origin and regulatory role of mast cells in asthma.

• DOI: 10.1097/aci.0000000000000703
• 发表时间: 2021-02-01
• 期刊: Current opinion in allergy and clinical immunology
• 影响因子: 2.8

Identification of mast cell progenitor cells in the airways of individuals with allergic asthma.

过敏性哮喘患者气道中肥大细胞祖细胞的鉴定。

• DOI: 10.1111/all.15498
• 发表时间: 2023
• 期刊: Allergy
• 影响因子: 12.4
• 作者: Murphy,RyanC;Chow,Yu-Hua;Lai,Ying;Al-Shaikhly,Taha;Petroni,DanielH;Black,Michele;Hamerman,JessicaA;Lacy-Hulbert,Adam;Piliponsky,AdrianM;Hallstrand,TealS
• 通讯作者: Hallstrand,TealS

Location of eosinophils in the airway wall is critical for specific features of airway hyperresponsiveness and T2 inflammation in asthma.

• DOI: 10.1183/13993003.01865-2021
• 发表时间: 2022-08
• 期刊: The European respiratory journal

Identification of Epithelial Phospholipase A2 Receptor 1 as a Potential Target in Asthma.

• DOI: 10.1165/rcmb.2015-0150oc
• 发表时间: 2016-12
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: J. Nolin;H. Ogden;Y. Lai;W. Altemeier;C. Frevert;James G. Bollinger;Gajendra S. Naika;A. Kicic;S. Stick;G. Lambeau;W. Henderson;M. Gelb;T. Hallstrand

Intravascular Leukocyte Labeling Refines the Distribution of Myeloid Cells in the Lung in Models of Allergen-induced Airway Inflammation.

• DOI: 10.4049/immunohorizons.2300059
• 发表时间: 2023-12-01
• 期刊: ImmunoHorizons
• 作者: Chow YH;Murphy RC;An D;Lai Y;Altemeier WA;Manicone AM;Hallstrand TS
• 通讯作者: Hallstrand TS