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Dexamethasone prevents virus-induced hyperresponsiveness via multiple mechanisms

¹Department of Environmental Health Sciences, Bloomberg School of Public Health, and ²Division of Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205

Submitted 14 February 2003 ; accepted in final form 17 April 2003

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 µg/kg ip) 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 µg/kg ip) 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 µg/kg ip) 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.

M₂ receptor function; glucocorticoids; vagus nerves; asthma

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