Identifying mechanisms and reversibility of eosinophil-induced airway hyperinnervation 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。 呼吸道神经控制着这些反应。最近，我们发现嗜酸性粒细胞，这是一个定义特征 大多数哮喘患者的呼吸道炎症，哮喘患者和男性患者感觉神经密度增加 老鼠。神经支配的增加会产生夸大的神经介导的反射性支气管收缩。这些 数据显示，嗜酸性粒细胞诱导的神经重塑在过度发展中起关键作用 哮喘时的支气管收缩。这一提议的中心假设是嗜酸性粒细胞增加 哮喘患者的呼吸道神经密度通过释放颗粒蛋白诱导神经营养因子，进而 促进神经生长，增强神经介导的反射性支气管收缩。我们将对此进行测试 三个目的的假说：1)确定嗜酸性粒细胞颗粒蛋白EPX和MBP在感觉中的作用 副交感神经重塑、神经营养因子表达和神经介导性反射 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支气管收缩试验 支气管收缩和3)确定哮喘患者的呼吸道过度神经支配是否被逆转 应用抗IL-5抗体前后支气管镜下呼吸道活检中呼吸道神经的测定 甲波利珠单抗。嗜酸性粒细胞耗尽的效果也将在已经建立了高度神经支配的小鼠身上进行测试。这个 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/或逆转哮喘患者的神经功能障碍。

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.