Identifying mechanisms and reversibility of eosinophil-induced airway hyperinnervation in asthma

确定哮喘中嗜酸性粒细胞诱导的气道过度神经支配的机制和可逆性

• 批准号: 10558693
• 负责人: Matthew G. Drake
• 金额: $ 65.19万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558693
• 关键词: 3-Dimensional; Abbreviations; Antibodies; Asthma; Attenuated; Biopsy; Brain-Derived Neurotrophic Factor; Bronchoconstriction; Cells; Confocal Microscopy; Cytoplasmic Granules; Data; Development; Drug Targeting; Eosinophil Granule Proteins; Eosinophilia; Functional disorder; Goals; Growth; Histologic; Human; IL5 gene; Image; Individual; Inhalation; Interleukin-5; Irritants; Knockout Mice; Length; Link; Lung; Measures; Mediating; Methodology; Methods; Morphology; Mus; Muscarinic Antagonists; Nerve; Nerve Growth Factor Receptors; Nerve Growth Factors; Neurons; Neuropeptides; Neurotransmitters; Neurotrophic Tyrosine Kinase Receptor Type 1; Optics; Pathway interactions; Phosphotransferases; Physiology; Proteins; Pyroglyphidae; Reflex action; Role; Sensory; Slice; Specimen; Stains; Structure; Structure of parasympathetic ganglion; Testing; Thick; Tissues; Transgenic Organisms; Tropomyosin; afferent nerve; airway epithelium; airway inflammation; asthmatic; computerized; density; eosinophil; eosinophil peroxidase; improved; innovation; mepolizumab; meter; mouse model; nerve supply; neurotrophic factor; overexpression; prevent; pulmonary function; receptor; reconstruction; respiratory smooth muscle; response; tiotropium

Asthma is characterized by excessive bronchoconstriction and a heightened sensitivity to inhaled irritants. Airway nerves control these responses. Recently, we found that eosinophils, which are a defining feature of airway inflammation in a majority of asthmatics, increased sensory nerve density in humans with asthma and in mice. Increased innervation produced exaggerated neuronally-mediated reflex bronchoconstriction. These data show that eosinophil-induced nerve remodeling has a key role in the development of excessive bronchoconstriction in asthma. The central hypothesis of this proposal is that eosinophils increase airway nerve density in asthma by releasing granule proteins that induce neurotrophins, which in turn promote nerve growth and potentiate nerve-mediated reflex bronchoconstriction. We will test this hypothesis in three aims that will 1) determine the role of eosinophil granule proteins EPX and MBP in sensory and parasympathetic nerve remodeling, neurotrophin expression and nerve-mediated reflex bronchoconstriction 2) test which neurotrophins mediate eosinophil-induced nerve remodeling and reflex bronchoconstriction and 3) determine whether airway hyperinnervation is reversed in humans with asthma by measuring airway nerves in bronchoscopic airway biopsies before and after initiation of the anti-IL5 antibody mepolizumab. Effects of eosinophil depletion will also be tested in mice with established hyperinnervation. The ultimate goals of this study are to discover new asthma mechanisms and to identify drug targets that will prevent and/or reverse effects of nerve dysfunction in asthma.

哮喘的特征是过度的支气管收缩和对吸入刺激物的高度敏感性。 呼吸道神经控制这些反应。最近，我们发现嗜酸性粒细胞，这是一个定义性的特点， 大多数哮喘患者的气道炎症，哮喘患者和哮喘患者的感觉神经密度增加， 小鼠增加神经支配产生夸张的神经介导的反射支气管收缩。这些 数据显示，嗜酸性粒细胞诱导的神经重塑在过度增生的发生中发挥关键作用 支气管收缩这个提议的中心假设是嗜酸性粒细胞增加 通过释放诱导神经营养素的颗粒蛋白， 促进神经生长和增强神经介导的反射性支气管收缩。我们将测试这个 这一假说有三个目的：1）确定嗜酸性粒细胞颗粒蛋白EPX和MBP在感觉神经元中的作用， 以及副交感神经重塑、神经营养因子表达和神经介导反射 支气管收缩2）神经营养因子介导嗜酸性粒细胞诱导的神经重塑和反射的试验 支气管收缩和3）确定是否气道过度神经支配在人类哮喘逆转， 在抗IL 5抗体开始之前和之后测量支气管镜气道活检中的气道神经 美泊利单抗还将在具有已建立的神经支配过度的小鼠中测试嗜酸性粒细胞耗竭的作用。的 这项研究的最终目标是发现新的哮喘机制，并确定药物靶点， 预防和/或逆转哮喘中神经功能障碍的作用。