Dexamethasone prevents virus-induced hyperresponsiveness via multiple mechanisms.
In the lungs, neuronal M2 muscarinic receptors inhibit acetylcholine release from the parasympathetic nerves. Parainfluenza virus infection causes loss of M2 receptor function, which increases acetylcholine release and vagally mediated bronchoconstriction. Because glucocorticoids are known to inhibit airway hyperresponsiveness, we tested whether dexamethasone (6.5 or 65 microg/kg i.p.) prevents virus-induced hyperresponsiveness and M2 receptor dysfunction in guinea pigs. In controls, pilocarpine, a muscarinic agonist, inhibited vagally induced bronchoconstriction, demonstrating functional M2 receptors. However, in virus-infected animals, pilocarpine failed to inhibit vagally induced bronchoconstriction, demonstrating M2 receptor dysfunction. Frequency-dependent bronchoconstriction was greater in virus-infected animals than in controls, indicating airway hyperresponsiveness. Low-dose dexamethasone (6.5 microg/kg i.p.) treatment prevented virus-induced airway hyperresponsiveness, ameliorated M2 receptor dysfunction, and decreased viral content in the lungs without inhibiting virus induced inflammation. High-dose dexamethasone (65 microg/kg i.p.) prevented virus-induced hyperresponsiveness, completely reversed M2 receptor dysfunction, decreased viral titers, and decreased virus-induced inflammation. This high-dose dexamethasone also increased M2 receptor function in uninfected animals. In conclusion, dexamethasone prevented virus-induced hyperresponsiveness and M2 receptor dysfunction via multiple mechanisms.
Moreno
Liliana
L
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Jacoby
David B
DB
Fryer
Allison D
AD
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D006168:Guinea Pigs; D008168:Lung / Q000294:innervation / Q000821:virology; D010862:Pilocarpine / Q000494:pharmacology; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology; D010253:Respirovirus Infections / Q000517:prevention & control*; D029082:Sendai virus; D014630:Vagus Nerve / Q000187:drug effects / Q000821:virology; D014779:Virus Replication / Q000187:drug effects*
D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D010862:Pilocarpine; D003907:Dexamethasone; D000109:Acetylcholine