OZONE INHIBITION OF NEURONAL M2 MUSCARINIC RECEPTORS

描述：(改编自申请人的摘要)：接触臭氧和 抗原导致呼吸道高反应性，这是由于增加释放 来自迷走神经的乙酰胆碱。释放量增加是由于神经功能障碍 神经元型M2受体，通常限制乙酰胆碱的释放， 从而限制了支气管收缩。M2受体功能丧失与 随后的过度活动依赖于嗜酸性粒细胞。类固醇通常是 用于治疗哮喘，假设它们是 消炎药。这项提案将解决类固醇是否能预防 保护神经元M2受体功能的高反应性。这个 地塞米松对体内高反应性和M2受体功能的影响 暴露在臭氧和抗原的前后都会进行检测。申请人 将确定地塞米松保护神经元的具体机制 M2受体功能；包括地塞米松是否抑制嗜酸性粒细胞 通过干扰细胞间黏附分子和血管细胞黏附分子的表达向肺内的神经迁移。 申请人还将确定地塞米松是否直接影响 神经元M2受体的产生(测量功能，免疫细胞化学， 原代培养的副交感神经。申请者还将 测试类固醇是否影响人类M2受体启动子的活性 (申请人已克隆)。最后，申请者将测试是否 在不涉及M2的模型中，地塞米松也可以防止高反应性 受体功能障碍(臭氧后3天)。预计这些研究 将使我们更好地理解高反应性 以及类固醇在对抗高反应性中的作用。自.以来 申请者已经证明神经元M2受体功能障碍。 暴露在臭氧中的人类和其他人已经展示了M2受体 哮喘患者的功能障碍，这些数据可能适用于 人类哮喘和暴露于污染物中的高反应性特征。

DESCRIPTION: (Adapted from the Applicant's Abstract): Exposure to ozone and to antigen causes airway hyperresponsiveness, which is due to increased release of acetylcholine from the vagus nerves. Increased release is due to dysfunction of neuronal M2 muscarinic receptors, which normally limit acetylcholine release, thus limiting bronchoconstriction. Loss of M2 receptor function and the subsequent hyperactivity is dependent upon eosinophils. Steroids are commonly used in the treatment of asthma on the assumption that they are anti-inflammatory. This proposal will address whether steroids prevent hyperreactivity by protecting neuronal M2 muscarinic receptor function. The effects of dexamethasone on hyperreactivity and M2 receptor function in vivo before and after exposure to ozone and antigen will be tested. The applicant will determine the specific mechanisms by which dexamethasone protects neuronal M2 receptor function; including whether dexamethasone inhibits eosinophil migration to nerves in the lungs by interfering with ICAM and VCAM expression. The applicant will also determine whether dexamethasone directly affects production of neuronal M2 receptors (measuring function, immunocytochemistry, M2 mRNA) in primary cultures of parasympathetic nerves. The applicant will also test whether steroids affect the activity of the human M2 receptor promoter (which the applicant has cloned). Finally the applicant will test whether dexamethasone also prevents hyperreactivity in a model that does not involve M2 receptor dysfunction (3 days post ozone). It is anticipated that these studies will lead to a greater understanding of the mechanisms by which hyperreactivity occurs, and the effects of steroids in countering hyperreactivity. Since the applicant has demonstrated that the neuronal M2 receptors are dysfunctional in man following exposure to ozone, and others have demonstrated M2 receptor dysfunction in asthmatic humans, these data may be applicable to the hyperreactivity characteristic of asthma and of exposure to pollutants in man.