Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma.
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.
Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
Ama-Tawiah
AT
Essilfie
Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
Jay C
JC
Horvat
Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
Richard Y
RY
Kim
Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
Jemma R
JR
Mayall
Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
James W
JW
Pinkerton
Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
Emma L
EL
Beckett
Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
Malcolm R
MR
Starkey
Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
Jodie L
JL
Simpson
Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
Paul S
PS
Foster
Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
Peter G
PG
Gibson
Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
Philip M
PM
Hansbro
D000658:Amoxicillin / Q000627:therapeutic use*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000209:etiology; D023521:Chlamydophila Infections / Q000150:complications / Q000188:drug therapy*; D016993:Chlamydophila pneumoniae; D017291:Clarithromycin / Q000627:therapeutic use*; D003907:Dexamethasone / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006192:Haemophilus Infections / Q000150:complications / Q000188:drug therapy*; D006193:Haemophilus influenzae; D051379:Mice; D008807:Mice, Inbred BALB C
D000900:Anti-Bacterial Agents; D005938:Glucocorticoids; D003907:Dexamethasone; D000658:Amoxicillin; D017291:Clarithromycin
Allergic lung disease; Asthma; Bacterial Infection; Respiratory Infection