BACKGROUND AND PURPOSE: 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. 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. 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. 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 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. CONCLUSIONS AND IMPLICATIONS: TNF-α is a key mediator of virus-induced M₂ muscarinic receptor dysfunction and airway hyperresponsiveness.
BACKGROUND AND PURPOSE: 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. 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. 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 humanneuroblastoma cells. M₂ 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 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. CONCLUSIONS AND IMPLICATIONS: TNF-α is a key mediator of virus-induced M₂ muscarinic receptor dysfunction and airway hyperresponsiveness.
Authors: Deborah A Sawatzky; Paul J Kingham; Emma Court; Bharathy Kumaravel; Allison D Fryer; David B Jacoby; W Graham McLean; Richard W Costello Journal: Am J Physiol Lung Cell Mol Physiol Date: 2002-06 Impact factor: 5.464
Authors: P H Howarth; K S Babu; H S Arshad; L Lau; M Buckley; W McConnell; P Beckett; M Al Ali; A Chauhan; S J Wilson; A Reynolds; D E Davies; S T Holgate Journal: Thorax Date: 2005-09-15 Impact factor: 9.139
Authors: Christopher T Ritchlin; Sally A Haas-Smith; Ping Li; David G Hicks; Edward M Schwarz Journal: J Clin Invest Date: 2003-03 Impact factor: 14.808
Authors: Becky J Proskocil; Donald A Bruun; David B Jacoby; Nico van Rooijen; Pamela J Lein; Allison D Fryer Journal: Am J Physiol Lung Cell Mol Physiol Date: 2013-02-01 Impact factor: 5.464