Retinoic acid prevents virus-induced airway hyperreactivity and M ₂ receptor dysfunction via anti-inflammatory and antiviral effects

Inhibitory M₂ 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 M₂ receptor dysfunction, we tested whether retinoic acid would prevent virus-induced airway hyperreactivity and prevent M₂ 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 M₂ receptor dysfunction. Treatment with all-trans retinoic acid (1 mg/kg) prevented virus-induced hyperreactivity and M₂ receptor dysfunction. However, retinoic acid also significantly reduced viral titers in the lungs and attenuated virus-induced lung inflammation. In vitro, retinoic acid decreased M₂ 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 M₂ receptor gene expression.