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Role of macrophages in virus-induced airway hyperresponsiveness and neuronal M₂ muscarinic receptor dysfunction

¹Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland 21205; ²Department of Physiology and Pharmacology, ⁴Division of Pulmonary and Critical Care Medicine, Oregon Health and Science University, Portland, Oregon 97239; and ³Department of Cell Biology and Immunology, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands

Submitted 22 December 2003 ; accepted in final form 29 January 2004

Viral infections exacerbate asthma. One of the pathways by which viruses trigger bronchoconstriction and hyperresponsiveness is by causing dysfunction of inhibitory M₂ muscarinic receptors on the airway parasympathetic nerves. These receptors normally limit acetylcholine (ACh) release from the parasympathetic nerves. Loss of M₂ receptor function increases ACh release, thereby increasing vagally mediated bronchoconstriction. Because viral infection causes an influx of macrophages into the lungs, we tested the role of macrophages in virus-induced airway hyperresponsiveness and M₂ receptor dysfunction. Guinea pigs infected with parainfluenza virus were hyperresponsive to electrical stimulation of the vagus nerves but not to intravenous ACh, indicating that hyperresponsiveness was due to increased release of ACh from the nerves. In addition, the muscarinic agonist pilocarpine no longer inhibited vagally induced bronchoconstriction, indicating M₂ receptor dysfunction. Treating animals with liposome-encapsulated dichloromethylene-diphosphonate depleted macrophages as assessed histologically. In these animals, viral infection did not cause airway hyperresponsiveness or M₂ receptor dysfunction. These data suggest that macrophages mediate virus-induced M₂ receptor dysfunction and airway hyperresponsiveness.

asthma; clodronate; liposomes; vagal; parasympathetic

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