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

Am J Physiol Lung Cell Mol Physiol. 2004 Jun;286(6):L1255-9. doi: 10.1152/ajplung.00451.2003.


Viral infections exacerbate asthma. One of the pathways by which viruses trigger bronchoconstriction and hyperresponsiveness is by causing dysfunction of inhibitory M(2) muscarinic receptors on the airway parasympathetic nerves. These receptors normally limit acetylcholine (ACh) release from the parasympathetic nerves. Loss of M(2) 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 M(2) 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 M(2) 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 M(2) receptor dysfunction. These data suggest that macrophages mediate virus-induced M(2) receptor dysfunction and airway hyperresponsiveness.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antimetabolites / pharmacology
  • Bronchial Hyperreactivity / immunology*
  • Bronchial Hyperreactivity / virology
  • Bronchoalveolar Lavage Fluid / cytology
  • Bronchoalveolar Lavage Fluid / immunology
  • Bronchoconstriction / immunology
  • Clodronic Acid / pharmacology
  • Female
  • Guinea Pigs
  • Liposomes
  • Macrophages, Alveolar / immunology*
  • Neurons / physiology
  • Parasympathetic Nervous System / cytology
  • Parasympathetic Nervous System / immunology
  • Parasympathetic Nervous System / physiopathology
  • Receptor, Muscarinic M2 / physiology*
  • Receptor, Muscarinic M3 / physiology
  • Respirovirus Infections / immunology*
  • Respirovirus Infections / physiopathology
  • Sendai virus*
  • Specific Pathogen-Free Organisms
  • Vagus Nerve / cytology
  • Vagus Nerve / immunology*
  • Vagus Nerve / physiopathology


  • Antimetabolites
  • Liposomes
  • Receptor, Muscarinic M2
  • Receptor, Muscarinic M3
  • Clodronic Acid