Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma (HYP2P.342)

Abstract

Abstract Background Steroid-insensitive endotypes of asthma are an important clinical problem requiring effective treatments. They are associated with non-eosinophilic inflammatory responses and bacterial infections. Macrolide therapy is effective in steroid-insensitive endotypes, such as non-eosinophilic asthma, however the mechanisms of how they work is unknown. Objectives To determine the efficacy of macrolide and non-macrolide antibiotic treatments in infection-induced, severe, steroid-insensitive allergic airways disease (SSIAAD). Methods Mouse models of Chlamydia and Haemophilus lung infection-induced SSIAAD were used to investigate the effects of clarithromycin and amoxicillin treatment on immune responses and AHR in steroid-sensitive AAD and SSIAAD compared to dexamethasone treatment. Results Amoxicillin and clarithromycin had similar anti-microbial effects on infection. Amoxicillin did not suppress either form of AAD, but restored steroid sensitivity in SSIAAD by reducing infection. In contrast, clarithromycin alone widely suppressed inflammation and AHR in both steroid-sensitive and SSIAAD. This occurred through reductions in both Th2 responses that drive steroid-sensitive, eosinophilic AAD, and TNF-α and IL-17 responses that induce neutrophilic SSIAAD. Conclusions Macrolides have broad anti-inflammatory effects that are independent of their anti-microbial effects. The specific responses suppressed are dependent upon the responses that dominate during disease