Role of TNF-α in virus-induced airway hyperresponsiveness and neuronal M2 muscarinic receptor dysfunction.
Br J Pharmacol
; 164(2b): 444-52, 2011 Sep.
Article
em En
| MEDLINE
| ID: mdl-21457223
ABSTRACT
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. EXPERIMENTALAPPROACH:
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. KEYRESULTS:
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Nervo Vago
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Fator de Necrose Tumoral alfa
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Hiper-Reatividade Brônquica
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Receptor Muscarínico M2
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Neurônios
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Br J Pharmacol
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
ENGLAND
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ESCOCIA
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GB
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GREAT BRITAIN
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INGLATERRA
/
REINO UNIDO
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SCOTLAND
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UK
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UNITED KINGDOM