Abstract

Infections with respiratory viruses induce exacerbations of asthma, increase acetylcholine release and potentiate vagally mediated bronchoconstriction by blocking inhibitory M₂ muscarinic receptors on parasympathetic neurons. Here we test whether virus-induced M₂ receptor dysfunction and airway hyperresponsiveness are tumour necrosis factor-alpha (TNF-α) dependent. Guinea pigs were pretreated with etanercept or phosphate-buffered saline 24 h before intranasal infection with parainfluenza. Four days later, pulmonary inflation pressure, heart rate and blood pressure were measured. M₂ receptor function was assessed by the potentiation by gallamine (an M₂ receptor antagonist) of bronchoconstriction caused by electrical stimulation of the vagus nerves and measured as increased pulmonary inflation pressure. Human airway epithelial cells were infected with influenza and TNF-α concentration in supernatant was measured before supernatant was applied to human neuroblastoma cells. M₂ receptor expression in these neuroblastoma cells was measured by qRT-PCR. Influenza-infected animals were hyperresponsive to vagal stimulation but not to intravenous ACh. Gallamine did not potentiate vagally induced bronchoconstriction in virus-infected animals, indicating M₂ receptor dysfunction. Etanercept prevented virus-induced airway hyperresponsiveness and M₂ receptor dysfunction, without changing lung viral titres. Etanercept caused a non-significant decrease in total cells, macrophages and neutrophils in bronchoalveolar lavage. Influenza infection significantly increased TNF-α release from isolated epithelial cells, sufficient to decrease M₂ receptors in neuroblastoma cells. This ability of supernatants from infected epithelial cells to inhibit M₂ receptor expression was blocked by etanercept. TNF-α is a key mediator of virus-induced M₂ muscarinic receptor dysfunction and airway hyperresponsiveness.

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