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.
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