Submitted on April 7, 2008
Revised on March 11, 2009
Accepted on May 14, 2009
Retinoic Acid Prevents Virus-induced Airway Hyperreactivity and M2 Receptor Dysfunction via Anti-inflammatory and Antiviral Effects
Liliana Moreno-Vinasco1, Norah G Verbout2, Allison D. Fryer3, and David B. Jacoby3*
1 University of Chicago
2 Oregon Health & Science University
3 Oregon Health and Science University
* To whom correspondence should be addressed. E-mail: jacobyd{at}ohsu.edu.
Inhibitory M2 muscarinic receptors on airway parasympathetic nerves normally limit acetylcholine release. Viral infections decrease M2 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 (1mg/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.
