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Am J Physiol Lung Cell Mol Physiol 279: L477-L486, 2000;
1040-0605/00 $5.00
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Vol. 279, Issue 3, L477-L486, September 2000

Substance P-induced airway hyperreactivity is mediated by neuronal M2 receptor dysfunction

Christopher M. Evans1, Kristen E. Belmonte1, Richard W. Costello1, David B. Jacoby2, Gerald J. Gleich3, and Allison D. Fryer1

1 Department of Environmental Health Sciences, School of Hygiene and Public Health, and 2 Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Johns Hopkins University, Baltimore, Maryland 21205; and 3 Departments of Immunology and Medicine, Mayo Clinic, Rochester, Minnesota 55905

Neuronal muscarinic (M2) receptors inhibit release of acetylcholine from the vagus nerves. Hyperreactivity in antigen-challenged guinea pigs is due to blockade of these M2 autoreceptors by eosinophil major basic protein (MBP) increasing the release of acetylcholine. In vivo, substance P-induced hyperactivity is vagally mediated. Because substance P induces eosinophil degranulation, we tested whether substance P-induced hyperreactivity is mediated by release of MBP and neuronal M2 receptor dysfunction. Pathogen-free guinea pigs were anesthetized and ventilated. Thirty minutes after intravenous administration of [Sar9,Met(O2)11]- substance P, guinea pigs were hyperreactive to vagal stimulation and M2 receptors were dysfunctional. The depletion of inflammatory cells with cyclophosphamide or the administration of an MBP antibody or a neurokinin-1 (NK1) receptor antagonist (SR-140333) all prevented substance P-induced M2 dysfunction and hyperreactivity. Intravenous heparin acutely reversed M2 receptor dysfunction and hyperreactivity. Thus substance P releases MBP from eosinophils resident in the lungs by stimulating NK1 receptors. Substance P-induced hyperreactivity is mediated by blockade of inhibitory neuronal M2 receptors by MBP, resulting in increased release of acetylcholine.

muscarinic receptors; eosinophil major basic protein; antigen challenge


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