Airway Sensory Nerves in Asthma

描述（由申请人提供）：反射性支气管收缩增强是哮喘的一个特征。我们最近在哮喘小鼠模型中显示了气道上皮感觉神经的加倍。这大大增加了反射性支气管收缩。消除嗜酸性粒细胞可防止神经支配和支气管收缩的增加。我们还发现，由于嗜酸性粒细胞产生的可溶性因子，嗜酸性粒细胞增加了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，这增加了反射性支气管收缩和咳嗽。我们提出了三个具体目标：具体目标#1：定义嗜酸性粒细胞介导的气道感觉神经支配的作用。在抗原激发模型和独特的嗜酸性粒细胞肺炎症转基因模型中，我们将使用我们的新型全坐式神经成像[8]来定义气道上皮感觉神经的嗜酸性粒细胞依赖性变化，以及P物质的含量，并测量TRPA1、TRPV1、TRPM8和ASIC3的表达。这些与气道反射性支气管收缩有关。特定目的2：通过靶向已确定疾病小鼠的嗜酸性粒细胞，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，允许诱导“按需”消融嗜酸性粒细胞（iPHIL小鼠）。我们还培养了缺乏糖皮质激素受体的嗜酸性粒细胞小鼠，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。特定目的#3：表征人类气道疾病的神经可塑性。与目的1和目的2相似的组织学终点将在特征明确的1)哮喘（轻度和重度）、2)咳嗽变异性哮喘和3)无哮喘咳嗽患者的活检中测量，并与正常志愿者进行比较。诱导痰和支气管肺泡灌洗嗜酸性过氧化物酶将作为可能的生物标志物进行测量。

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.