Abstract
Each year, approximately 20% of asthmatics in the United States experience acute symptom exacerbations, which commonly result from pulmonary viral infections. The majority of asthma exacerbations in very young children follow infection with respiratory syncytial virus (RSV). However, pathogenic mechanisms underlying induction of asthma exacerbations by RSV are not well understood. We therefore investigated the effect of post-sensitization RSV infection on lung function in ovalbumin (OVA)-sensitized BALB/c mice as a model of RSV asthma exacerbations. OVA sensitization of uninfected female BALB/c mice increased bronchoalveolar lavage fluid (BALF) eosinophil levels and induced airway hyperresponsiveness to the muscarinic agonist methacholine, as measured by the forced-oscillation technique. In contrast, intranasal infection with replication-competent RSV strain A2 for 2–8 days reduced BALF eosinophil counts and reversed airway hyperresponsiveness in a pertussis toxin-sensitive manner. BALF levels of the chemokine keratinocyte cytokine (KC; a murine homolog of interleukin-8) were elevated in OVA-sensitized, RSV-infected mice and reversal of methacholine hyperresponsiveness in these animals was rapidly inhibited by KC neutralization. Hyporesponsiveness could be induced in OVA-sensitized, uninfected mice by recombinant KC or the Gαi agonist melittin. These data suggest that respiratory syncytial virus induces KC-mediated activation of Gαi, resulting in cross-inhibition of Gαq-mediated M3-muscarinic receptor signaling and reversal of airway hyperresponsiveness. As in unsensitized mice, KC therefore appears to play a significant role in induction of airway dysfunction by respiratory syncytial virus. Hence, interleukin-8 may be a promising therapeutic target to normalize lung function in both asthmatics and non-asthmatics with bronchiolitis. However, the OVA-sensitized, RSV-infected mouse may not be an appropriate model for investigating the pathogenesis of viral asthma exacerbations.
Highlights
An estimated 300 million persons worldwide suffer from asthma [1]
We found that infection with respiratory syncytial virus (RSV) paradoxically reversed airway hyperresponsiveness to methacholine in a keratinocyte cytokine (KC)-dependent, pertussis toxin-sensitive fashion
The majority of asthma exacerbations in very young children result from RSV infection [3,5]
Summary
An estimated 300 million persons worldwide suffer from asthma [1]. Of the 20 million asthmatics in the United States alone, approximately 20% experience an acute deterioration of respiratory symptoms (an asthma exacerbation) in a single year [2]. While most asthma exacerbations are managed in the outpatient setting, more severe episodes may require hospitalization and can even prove fatal [1]. Viral infections are the most common cause of asthma exacerbations in both children and adults [3]. In children under the age of two years, the majority appear to be caused by respiratory syncytial virus (RSV), rhinovirus may predominate in older children and adults [4,5]
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