Airway Sensory Nerves in Asthma

哮喘中的气道感觉神经

基本信息

批准号：
8764525
负责人：
David B Jacoby
金额：
$ 79.05万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8764525
关键词：
Ablation Acids Acrolein Acute Afferent Neurons Alveolus Animals Anti-Cholinergics Antibodies Asthma Atopic Dermatitis Biological Markers Biopsy Bronchoalveolar Lavage Bronchoconstriction Characteristics Chronic Obstructive Airway Disease Coughing Diphtheria Toxin Disease Distal Epithelial Event Glucocorticoid Receptor Growth Human Image In Vitro Interleukin-5 Left Length Leukocytes Lung Measures Mediating Mediator of activation protein Menthol Methods Modeling Mouse Strains Mus Nerve Neuronal Plasticity Neurons Pathway interactions Patients Pneumonia Process Proteins Pyroglyphidae Reflex action Sensory Skin Spinal Ganglia Sputum Staining method Stains Steroids Structure Structure of parenchyma of lung Substance P TRPV1 gene Transgenic Mice Transgenic Model Variant Wild Type Mouse afferent nerve antigen challenge base capsaicin receptor computerized eosinophil eosinophil peroxidase mouse model nerve supply neuromechanism neurotrophic factor novel prevent public health relevance receptor recombinase reconstruction volunteer

项目摘要

DESCRIPTION (provided by applicant): Increased reflex bronchoconstriction is a characteristic of asthma. We have recently shown a doubling of airway epithelial sensory nerves in a mouse model of asthma. This increased reflex bronchoconstriction substantially. Eliminating eosinophils prevented the increases in both innervation and bronchoconstriction. We also showed that eosinophils increase the growth of cultured dorsal root ganglion sensory neurons, due to a soluble factor produced by the eosinophils. Thus eosinophils increase airway sensory innervation, and this may participate in both the bronchoconstriction and the cough that are common in asthma. We hypothesize that eosinophils promote airway sensory nerve growth and this increases reflex bronchoconstriction and cough. We propose three specific aims: SPECIFIC AIM #1: To define eosinophil-mediated effects on airway sensory innervation. In both an antigen challenge model and unique transgenic models of eosinophilic pulmonary inflammation, we will use our novel whole-mount nerve imaging [8] to define eosinophil-dependent changes in airway epithelial sensory innervation, as well as on substance P content, and TRPA1, TRPV1, TRPM8, and ASIC3 expression will be measured. These will be correlated with airway reflex bronchoconstriction. SPECIFIC AIM #2: To determine the reversibility of these pulmonary remodeling events by targeting eosinophils in mice with established disease. We will use our new strains of mice that allow inducible "on demand" ablation of eosinophils (the iPHIL mouse). We have also generated mice with eosinophils that lack the glucocorticoid receptor, allowing us to determine whether the effects of steroid treatment are mediated by suppressing eosinophils or via eosinophil independent pathways. SPECIFIC AIM #3: To characterize neural plasticity in human airway disease. Similar histological endpoints as in aims 1 and 2 will be measured in biopsies from well-characterized patients with 1) asthma (mild and severe), 2) cough-variant asthma, and 3) cough without asthma, comparing these with normal volunteers. Induced sputum and bronchoalveolar lavage eosinophil peroxidase will be measured as possible biomarkers.

描述（由申请人提供）：反射性支气管收缩增加是哮喘的一个特征。我们最近在哮喘小鼠模型中发现气道上皮感觉神经加倍。这大大增加了反射性支气管收缩。消除嗜酸性粒细胞可以防止神经支配和支气管收缩的增加。我们还表明，由于嗜酸性粒细胞产生的可溶性因子，嗜酸性粒细胞会增加培养的背根神经节感觉神经元的生长。因此，嗜酸性粒细胞增加气道感觉神经支配，这可能参与哮喘中常见的支气管收缩和咳嗽。我们假设嗜酸性粒细胞促进气道感觉神经生长，从而增加反射性支气管收缩和咳嗽。我们提出三个具体目标：具体目标#1：定义嗜酸性粒细胞介导的对气道感觉神经支配的影响。在抗原攻击模型和嗜酸性肺部炎症的独特转基因模型中，我们将使用我们新颖的整体神经成像[8]来定义气道上皮感觉神经支配中嗜酸性粒细胞依赖性的变化，以及P物质含量和TRPA1 、TRPV1、TRPM8 和 ASIC3 表达将被测量。这些将与气道反射性支气管收缩相关。具体目标#2：通过针对患有已知疾病的小鼠中的嗜酸性粒细胞来确定这些肺重塑事件的可逆性。我们将使用我们的新小鼠品系，它们可以“按需”诱导消除嗜酸性粒细胞（iPHIL 小鼠）。我们还培育出了缺乏糖皮质激素受体的嗜酸性粒细胞小鼠，这使我们能够确定类固醇治疗的效果是通过抑制嗜酸性粒细胞还是通过嗜酸性粒细胞独立途径介导的。具体目标#3：表征人类气道疾病中的神经可塑性。与目标 1 和 2 中类似的组织学终点将在 1) 哮喘（轻度和重度）、2) 咳嗽变异性哮喘和 3) 咳嗽非哮喘患者的活检中测量，并将这些患者与正常志愿者进行比较。诱导痰和支气管肺泡灌洗液中的嗜酸性粒细胞过氧化物酶将作为可能的生物标志物进行测量。