Airway Eosinophil Activation by Anticholinergic Therapy

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DESCRIPTION (provided by applicant): While the addition of anticholinergics to (-agonists has been shown to be beneficial in acute asthma attacks, the use of anticholinergics in the management of chronic stable asthma has been disappointing, and seems to add little to treatment with other agents. We have recently made the surprising observation that treating ovalbumin sensitized animals with the anticholinergic atropine at the time of antigen challenge markedly increases vagally mediated hyperreactivity measured 24 hours later (by which time the atropine has worn off). Histological examination at that time shows markedly increased eosinophil activation, as reflected in increased extracellular deposition of eosinophil major basic protein. Thus the anticholinergic treatment made the airway disease worse. We hypothesize that anticholinergic medications block muscarinic receptors on eosinophils that normally function to limit eosinophil activation. Blocking these muscarinic receptors on the eosinophils increases eosinophil activation and worsens airway disease. Delineating the effects of acetylcholine on eosinophil function as well as the specific muscarinic receptor responsible will have substantial clinical implications. If the specific muscarinic receptor responsible for inhibiting eosinophil activation is different from the M3 receptor (which is responsible for smooth muscle contraction), then selective antagonism of the M3 receptor would allow bronchodilitation without potentiating eosinophil activation. Alternatively, if this is not possible, activation of eosinophils by anticholinergics might provide a rationale for combining anticholinergics with treatments aimed at limiting eosinophil activation, such as CCR3 antagonists. We propose two specific aims: Specific Aim 1: To use selective antagonists to determine which subtype of muscarinic receptor is responsible for the ability of anticholinergics to potentiate ovalbumin induced hyperreactivity to vagal stimulation. Specific Aim 2: To confirm the presence of muscarinic receptors on guinea pig eosinophils, to extend these observations to human eosinophils, and to determine the effects of stimulation of eosinophil muscarinic receptors on eosinophil activation in vitro. PROJECT NARRATIVE: Drugs that block substances released by nerves in the lungs are used to treat asthma. We have found that these drugs may activate white blood cells to make the asthma worse. In this project, we will find out how these drugs are making the asthma worse and, in so doing, find out how to design a treatment that won't have these negative effects.