OZONE INHIBITION OF NEURONAL M2 MUSCARINIC RECEPTORS

描述：（改编自申请人的摘要）：暴露于臭氧和 抗原引起气道高反应性，这是由于增加释放的 迷走神经的乙酰胆碱增加的释放是由于 神经元M2毒蕈碱受体，通常限制乙酰胆碱释放， 从而限制支气管收缩。M2受体功能丧失， 随后的活动过度依赖于嗜酸性粒细胞。类固醇通常是 用于治疗哮喘的假设， 消炎药该提案将解决类固醇是否可以预防 高反应性通过保护神经元M2毒蕈碱受体功能。的 地塞米松对高反应性和M2受体功能的影响 在暴露于臭氧和抗原之前和之后将进行测试。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ICAM和VCAM的表达而迁移到肺中的神经。 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， M2 mRNA）。申请人还将 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，申请人将测试是否 地塞米松还可预防不涉及M2的模型中的高反应性 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 发生，以及类固醇在对抗高反应性中的作用。以来 申请人已经证明，神经元M2受体功能障碍， 人暴露于臭氧，和其他人已经证明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所特有高反应性。

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.