Azithromycin modulates viral-induced asthma exacerbation by targeting the innate immune response

Abstract

Viral respiratory infections trigger exacerbation of asthma, characterized by an exaggerated inflammatory response and airway hyperresponsiveness (AHR) resulting in worsening disease symptoms and a decline in lung function. Conventional therapies such as inhaled corticosteroids often inadequately control symptoms of asthma exacerbation. Azithromycin (AZM) has been shown to have therapeutic benefits for several respiratory diseases (COPD, cystic fibrosis, asthma). Although antimicrobial AZM may have other mechanisms of action, its therapeutic benefit for asthma exacerbation remains poorly understood. Previously, we have established a respiratory syncytial virus (RSV)-induced model of asthma exacerbation. In this model, infection of OVA-sensitized/challenged mice with RSV significantly increased AHR, the number of infiltrating inflammatory macrophages and levels of inflammatory cytokines (TNFa, IFN?, IL-27) compared to controls. Furthermore, these clinical features of exacerbation were resistant to steroid treatment. Depletion of lung macrophages or neutralisation of each cytokine was shown to suppress RSV-induced AHR. In this study, OVA-sensitized/challenged mice were treated with AZM after inoculation with RSV. We found that AZM treatment not only suppressed AHR, but also reduced all key markers of exacerbation. Furthermore, TNFa-produced by alveolar macrophages was reduced with AZM treatment. Recombinant TNFa administration could reverse exacerbation in the presence of AZM. Our findings highlight the mechanism of AZM suppressed AHR and airway inflammation in RSV-induced asthma exacerbation through targeting the innate immune response linked to alveolar macrophages and TNFa production.