Abstract
Asthma is a chronic inflammatory airways disease in which respiratory viral infections frequently trigger exacerbations. Current treatment of asthma with combinations of inhaled corticosteroids and long acting beta2 agonists improves asthma control and reduces exacerbations but what impact this might have on innate anti-viral immunity is unclear. We investigated the in vitro effects of asthma drugs on innate anti-viral immunity. Peripheral blood mononuclear cells (PBMC) from healthy and asthmatic donors were cultured for 24 hours with the Toll-like receptor 7 agonist, imiquimod, or rhinovirus 16 (RV16) in the presence of budesonide and/or formoterol. Production of proinflammatory cytokines and expression of anti-viral intracellular signalling molecules were measured by ELISA and RT-PCR respectively. In PBMC from healthy donors, budesonide alone inhibited IP-10 and IL-6 production induced by imiquimod in a concentration-dependent manner and the degree of inhibition was amplified when budesonide and formoterol were used in combination. Formoterol alone had little effect on these parameters, except at high concentrations (10−6 M) when IL-6 production increased. In RV16 stimulated PBMC, the combination of budesonide and formoterol inhibited IFNα and IP-10 production in asthmatic as well as healthy donors. Combination of budesonide and formoterol also inhibited RV16-stimulated expression of the type I IFN induced genes myxovirus protein A and 2′, 5′ oligoadenylate synthetise. Notably, RV16 stimulated lower levels of type Myxovirus A and oligoadenylate synthase in PBMC of asthmatics than control donors. These in vitro studies demonstrate that combinations of drugs commonly used in asthma therapy inhibit both early pro-inflammatory cytokines and key aspects of the type I IFN pathway. These findings suggest that budesonide and formoterol curtail excessive inflammation induced by rhinovirus infections in patients with asthma, but whether this inhibits viral clearance in vivo remains to be determined.
Highlights
Asthma is a chronic inflammatory disease of the lower airways affecting up to 300 million individuals worldwide and posing a significant burden on health care systems in both western and developing countries [1]
In this study we aimed to investigate the effect of combinations of the glucocorticoid, budesonide, and the long acting beta2 agonist, formoterol, on innate immune responses to rhinovirus
Inhaled corticosteroids and long acting beta2 agonists form the cornerstones of current asthma therapy [9,33], and even in previously healthy individuals these agents are sometimes used in an effort to reduce persistent airway symptoms such as prolonged coughing after respiratory viral infections
Summary
Asthma is a chronic inflammatory disease of the lower airways affecting up to 300 million individuals worldwide and posing a significant burden on health care systems in both western and developing countries [1]. The major medical burden and health care costs of asthma including morbidity and mortality occur during acute exacerbations [3,4]. Current asthma treatment usually includes a combination of inhaled corticosteroids and long acting beta agonists. These medications are effective at controlling symptoms of asthma and they reduce but do not eliminate asthma exacerbations [9,10,11]. The excessive pro-inflammatory responses in asthmatic individuals could contribute to the immunopathology of acute episodes of asthma [15]
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