Airway Sensory Nerves in Asthma

描述（由申请方提供）：反射性支气管收缩增加是哮喘的特征。我们最近在小鼠哮喘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。消除嗜酸性粒细胞阻止了神经支配和支气管收缩的增加。我们还发现，嗜酸性粒细胞增加培养的背根神经节感觉神经元的生长，由于嗜酸性粒细胞产生的可溶性因子。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：确定嗜酸性粒细胞介导的气道感觉神经支配的影响。在嗜酸性粒细胞肺部炎症的抗原激发模型和独特的转基因模型中，我们将使用我们的新型整体神经成像[8]来确定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，并测量TRPA 1，TRPV 1，TRPM 8和ASIC 3表达。这些将与气道反射性支气管收缩相关。具体目的#2：通过靶向已确诊疾病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品系的小鼠，允许诱导的“按需”消融嗜酸性粒细胞（iPHIL小鼠）。我们还产生了缺乏糖皮质激素受体的嗜酸性粒细胞的小鼠，使我们能够确定类固醇治疗的效果是否是通过抑制嗜酸性粒细胞或通过嗜酸性粒细胞独立的途径介导的。具体目标#3：描述人类气道疾病中的神经可塑性。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）咳嗽不伴哮喘患者的活检中测量与目标1和2相似的组织学终点，并将其与正常志愿者进行比较。将测量诱导痰和支气管肺泡灌洗液嗜酸性粒细胞过氧化物酶作为可能的生物标志物。

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.