Abstract
BackgroundExacerbations 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.Methodology/Principal FindingsWe 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/SignificanceOur 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.
Highlights
Exacerbations of asthma are defined as a worsening of clinical symptoms such as wheeze, shortness of breath, chest tightness, bronchial hyper-responsiveness and airflow obstruction and can occur in all asthmatic patients, regardless of disease severity [1, 2]
I-bromoand extra-terminal (BET)-762 administration inhibits the development of steroid resistant inflammation and airways hyperresponsiveness (AHR) in interferon γ (IFNγ)/LPS-treated mice
Vehicle administration alone did not induce AHR and vehicle administration in IFNγ/LPS-stimulated mice had no effect on AHR (Fig 1.A and 1.B)
Summary
Exacerbations of asthma are defined as a worsening of clinical symptoms such as wheeze, shortness of breath, chest tightness, bronchial hyper-responsiveness and airflow obstruction and can occur in all asthmatic patients, regardless of disease severity [1, 2]. Neutrophils are prominent in cellular infiltrates and increased pro-inflammatory cytokines (e.g. IL-8, TNFα, IFNγ and MCP-1) are a feature of acute exacerbations in asthmatic patients following viral and bacterial infections [5,6,7,8,9]. 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. We have established a mouse model of respiratory syncytial virus (RSV)-induced exacerbation of asthma, which exhibits macrophage-dependent, steroid-resistant lung disease. We hypothesised that BET proteins may be involved in the regulation of AHR and airway inflammation in our steroid-resistant exacerbation models
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