Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma

Abstract

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 steroidinsensitive 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.

Macrolide Therapy and Alveolar Hemorrhage Secondary to Granulomatosis With Polyangiitis

“…As well as being effective against many grampositive and some gram-negative bacteria, their immunomodulatory properties are well-described [8]. Various agents from this class of drug are used in the treatment of chronic inflammatory respiratory diseases [9], with anti-inflammatory effects that are likely independent of their antimicrobial action [10]. Experimental and clinical studies show that macrolides cause increased leucocyte apoptosis, reduced cytokine expression, and impaired T-cell proliferation and signalling [11].…”

Addressing corticosteroid insensitivity in adults with asthma

“…Additionally, macrolides may restore corticosteroid sensitivity by inhibiting PI3K activation [116] and TNFα/IL-17 immune responses [117]. Two recent exploratory clinical trials have investigated the effects of macrolides in non-eosinophilic asthma associated with corticosteroid insensitivity.…”

Novel approaches to the management of noneosinophilic asthma

“…The mechanism of action of macrolides in the treatment of airway diseases is not known, but could be due to antibacterial or anti-inflammatory actions, which include inhibition of nuclear factor (NF)-κB and other transcription factors as well as reduction in neutrophil migration or function [Culic et al 2001;Fujitani and Trifilieff, 2003;Simpson et al 2008;Cameron et al 2012;Kobayashi et al 2013]. Macrolides have additional potentially beneficial properties including antiviral actions [Gielen et al 2010;Schögler et al 2015] and an ability to restore corticosteroid sensitivity by inhibiting the phosphoinositide 3-kinase (PI3K) pathway and restoring histone deacetylase (HDAC)2 activity [Spahn et al 2001;Kobayashi et al 2013;Hao et al 2015] and by attenuating TNFα and IL-17 immune responses [Essilfie et al 2015]. Two recent exploratory clinical trials have investigated the effects of macrolides in noneosinophilic asthma.…”