BACKGROUND AND PURPOSE Infections with respiratory viruses induce exacerbations of asthma, increase acetylcholine release and potentiate vagally mediated bronchoconstriction by blocking inhibitory M 2 muscarinic receptors on parasympathetic neurons. Here we test whether virus-induced M 2 receptor dysfunction and airway hyperresponsiveness are tumour necrosis factor-alpha (TNF-α) dependent. EXPERIMENTAL APPROACH 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. M 2 receptor function was assessed by the potentiation by gallamine (an M 2 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. M 2 receptor expression in these neuroblastoma cells was measured by qRT-PCR. KEY RESULTS 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 M 2 receptor dysfunction. Etanercept prevented virus-induced airway hyperresponsiveness and M 2 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 M 2 receptors in neuroblastoma cells. This ability of supernatants from infected epithelial cells to inhibit M 2 receptor expression was blocked by etanercept. CONCLUSIONS AND IMPLICATIONS TNF-α is a key mediator of virus-induced M 2 muscarinic receptor dysfunction and airway hyperresponsiveness.
- airway hyperreactivity
ASJC Scopus subject areas