RT Journal Article
SR Electronic
T1 Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma
JF Thorax
JO Thorax
FD BMJ Publishing Group Ltd and British Thoracic Society
SP 458
OP 467
DO 10.1136/thoraxjnl-2014-206067
VO 70
IS 5
A1 Ama-Tawiah Essilfie
A1 Jay C Horvat
A1 Richard Y Kim
A1 Jemma R Mayall
A1 James W Pinkerton
A1 Emma L Beckett
A1 Malcolm R Starkey
A1 Jodie L Simpson
A1 Paul S Foster
A1 Peter G Gibson
A1 Philip M Hansbro
YR 2015
UL http://thorax.bmj.com/content/70/5/458.abstract
AB Background Steroid-insensitive endotypes of asthma are an important clinical problem and effective therapies are required. They are associated with bacterial infection and non-eosinophilic inflammatory responses in the asthmatic lung. Macrolide therapy is effective in steroid-insensitive endotypes, such as non-eosinophilic asthma. However, whether the effects of macrolides are due to antimicrobial or anti-inflammatory mechanisms is not known. Objective To determine and assess the efficacy of macrolide (ie, clarithromycin) and non-macrolide (ie, amoxicillin) antibiotic treatments in experimental models of infection-induced, severe, steroid-insensitive neutrophilic allergic airways disease (SSIAAD), compared with steroid-sensitive AAD and to delineate the antimicrobial and anti-inflammatory effects of macrolide therapy. Methods We developed and used novel mouse models of Chlamydia and Haemophilus lung infection-induced SSIAAD. We used these models to investigate the effects of clarithromycin and amoxicillin treatment on immune responses and airways hyper-responsiveness (AHR) in Ova-induced, T helper lymphocyte (Th) 2 -associated steroid-sensitive AAD and infection-induced Th1/Th17-associated SSIAAD compared with dexamethasone treatment. Results Clarithromycin and amoxicillin had similar antimicrobial effects on infection. Amoxicillin did attenuate some features, but did not broadly suppress either form of AAD. It did restore steroid sensitivity in SSIAAD by reducing infection. In contrast, clarithromycin alone widely suppressed inflammation and AHR in both steroid-sensitive AAD and SSIAAD. This occurred through reductions in Th2 responses that drive steroid-sensitive eosinophilic AAD and tumour necrosis factor α and interleukin 17 responses that induce SSIAAD. Conclusions Macrolides have broad anti-inflammatory effects in AAD that are likely independent of their antimicrobial effects. The specific responses that are suppressed are dependent upon the responses that dominate during AAD.