title: Bromodomain and Extra Terminal (BET) Inhibitor Suppresses Macrophage-Driven Steroid-Resistant Exacerbations of Airway Hyper-Responsiveness and Inflammation.
abstract: BACKGROUND
  Exacerbations of asthma are linked to significant decline in lung function and are often poorly controlled by corticosteroid treatment. Clinical investigations indicate that viral and bacterial infections play crucial roles in the onset of steroid-resistant inflammation and airways hyperresponsiveness (AHR) that are hallmark features of exacerbations. We have previously shown that interferon γ (IFNγ) and lipopolysaccharide (LPS) cooperatively activate pulmonary macrophages and induce steroid-resistant airway inflammation and AHR in mouse models. Furthermore, we have established a mouse model of respiratory syncytial virus (RSV)-induced exacerbation of asthma, which exhibits macrophage-dependent, steroid-resistant lung disease. Emerging evidence has demonstrated a key role for bromo- and extra-terminal (BET) proteins in the regulation of inflammatory gene expression in macrophages. We hypothesised that BET proteins may be involved in the regulation of AHR and airway inflammation in our steroid-resistant exacerbation models.
  
  
  RESULTS
  We investigated the effects of a BET inhibitor (I-BET-762) on the development of steroid-resistant AHR and airway inflammation in two mouse models. I-BET-762 administration decreased macrophage and neutrophil infiltration into the airways, and suppressed key inflammatory cytokines in both models. I-BET treatment also suppressed key inflammatory cytokines linked to the development of steroid-resistant inflammation such as monocyte chemoattractant protein 1 (MCP-1), keratinocyte-derived protein chemokine (KC), IFNγ, and interleukin 27 (IL-27). Attenuation of inflammation was associated with suppression of AHR.
  
  
  CONCLUSIONS
  Our results suggest that BET proteins play an important role in the regulation of steroid-resistant exacerbations of airway inflammation and AHR. BET proteins may be potential targets for the development of future therapies to treat steroid-resistant inflammatory components of asthma.
authors.affiliation: Priority Research Centre for Healthy Lungs, School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine and Hunter Medical Research Institute, The University of Newcastle, Callaghan, NSW 2300, Australia.
authors.forename: Thi Hiep
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: Priority Research Centre for Healthy Lungs, School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine and Hunter Medical Research Institute, The University of Newcastle, Callaghan, NSW 2300, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Maltby
authors.affiliation: Priority Research Centre for Healthy Lungs, School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine and Hunter Medical Research Institute, The University of Newcastle, Callaghan, NSW 2300, Australia.
authors.forename: Fiona
authors.initials: F
authors.lastname: Eyers
authors.affiliation: Priority Research Centre for Healthy Lungs, School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine and Hunter Medical Research Institute, The University of Newcastle, Callaghan, NSW 2300, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.affiliation: Priority Research Centre for Healthy Lungs, School of Biomedical Sciences & Pharmacy, Faculty of Health and Medicine and Hunter Medical Research Institute, The University of Newcastle, Callaghan, NSW 2300, Australia.
authors.forename: Ming
authors.initials: M
authors.lastname: Yang