Retinoic acid prevents virus-induced airway hyperreactivity and M2 receptor dysfunction via anti-inflammatory and antiviral effects

Am J Physiol Lung Cell Mol Physiol. 2009 Aug;297(2):L340-6. doi: 10.1152/ajplung.90267.2008. Epub 2009 May 22.


Inhibitory M(2) muscarinic receptors on airway parasympathetic nerves normally limit acetylcholine release. Viral infections decrease M(2) receptor function, increasing vagally mediated bronchoconstriction. Since retinoic acid deficiency causes M(2) receptor dysfunction, we tested whether retinoic acid would prevent virus-induced airway hyperreactivity and prevent M(2) receptor dysfunction. Guinea pigs infected with parainfluenza virus were hyperreactive to electrical stimulation of the vagus nerves, but not to intravenous acetylcholine, indicating that hyperreactivity was due to increased release of acetylcholine from parasympathetic nerves. The muscarinic agonist pilocarpine, which inhibits vagally mediated bronchoconstriction in control animals, no longer inhibited vagally induced bronchoconstriction, demonstrating M(2) receptor dysfunction. Treatment with all-trans retinoic acid (1 mg/kg) prevented virus-induced hyperreactivity and M(2) receptor dysfunction. However, retinoic acid also significantly reduced viral titers in the lungs and attenuated virus-induced lung inflammation. In vitro, retinoic acid decreased M(2) receptor mRNA expression in both human neuroblastoma cells and primary cultures of airway parasympathetic neurons. Thus, the protective effects of retinoic acid on airway function during viral infection appear to be due to anti-inflammatory and antiviral mechanisms, rather than to direct effects on M(2) receptor gene expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Bronchial Hyperreactivity* / drug therapy
  • Bronchial Hyperreactivity* / immunology
  • Bronchial Hyperreactivity* / virology
  • Bronchoconstriction / drug effects
  • Bronchoconstriction / immunology
  • Cell Line, Tumor
  • Cholinergic Agents / pharmacology
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / genetics
  • Female
  • Gene Expression / drug effects
  • Guinea Pigs
  • Humans
  • Interleukin-8 / genetics
  • Muscarinic Agonists / pharmacology
  • Neuroblastoma
  • Neurons / drug effects
  • Neurons / physiology
  • Paramyxoviridae Infections* / complications
  • Paramyxoviridae Infections* / drug therapy
  • Paramyxoviridae Infections* / immunology
  • Pilocarpine / pharmacology
  • Receptor, Muscarinic M2 / genetics
  • Receptor, Muscarinic M2 / metabolism*
  • Receptors, Immunologic
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / drug effects*
  • Respiratory Mucosa / innervation
  • Trachea / cytology
  • Trachea / drug effects
  • Trachea / innervation
  • Tretinoin / pharmacology*
  • Virus Replication / drug effects


  • Antineoplastic Agents
  • Cholinergic Agents
  • Interleukin-8
  • Muscarinic Agonists
  • Receptor, Muscarinic M2
  • Receptors, Immunologic
  • Pilocarpine
  • Tretinoin
  • RIGI protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Acetylcholine