Double-stranded RNA causes airway hyperreactivity and neuronal M2 muscarinic receptor dysfunction.
Viral infection causes dysfunction of inhibitory M2 muscarinic receptors (M2Rs) on parasympathetic nerves, leading to airway hyperreactivity. The mechanisms of M2R dysfunction are incompletely understood. Double-stranded RNA (dsRNA), a product of viral replication, promotes the expression of interferons. Interferon-gamma decreases M2R gene expression in cultured airway parasympathetic neurons. In this study, guinea pigs were treated with dsRNA (1 mg/kg ip) on 2 consecutive days. Twenty-four hours later, anesthetized guinea pigs had dysfunctional M2Rs and were hyperresponsive to electrical stimulation of the vagus nerves, in the absence of inflammation. DsRNA did not affect either cholinesterase or the function of postjunctional M3 muscarinic receptors on smooth muscle. M2Rs on the nerves supplying the heart were also dysfunctional, but M2Rs on the heart muscle itself functioned normally. Thus dsRNA causes increased bronchoconstriction and bradycardia via increased release of ACh from the vagus nerves because of loss of M2R function on parasympathetic nerves in the lungs and heart. Production of dsRNA may be a mechanism by which viruses cause dysfunction of neuronal M2Rs and airway hyperreactivity.
Bowerfind
William M L
WM
Division of Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Fryer
Allison D
AD
Jacoby
David B
DB
D000818:Animals; D001249:Asthma / Q000503:physiopathology / Q000821:virology; D016535:Bronchial Hyperreactivity / Q000503:physiopathology* / Q000821:virology; D018893:Bronchoalveolar Lavage; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate; D007274:Injections, Intraperitoneal; D009474:Neurons / Q000502:physiology* / Q000821:virology; D010275:Parasympathetic Nervous System / Q000166:cytology / Q000502:physiology / Q000821:virology; D010850:Picornaviridae Infections / Q000503:physiopathology; D012330:RNA, Double-Stranded / Q000494:pharmacology*; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000235:genetics* / Q000378:metabolism*; D012229:Rhinovirus; D013047:Specific Pathogen-Free Organisms; D014630:Vagus Nerve / Q000166:cytology / Q000502:physiology
D012330:RNA, Double-Stranded; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic