- Title
- Modeling of respiratory syncytial virus-induced exacerbation of allergic airways disease
- Creator
- Nguyen, Thi Hiep
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2017
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Asthma is a chronic inflammatory disorder of the airways characterised by clinical symptoms such as wheeze, shortness of breath, airflow obstruction, mucus hypersecretion and airway hyper-responsiveness (AHR). Numerous factors contribute to the pathogenesis of asthma, including respiratory infections, allergens, pollution and smoking. These factors can trigger asthma exacerbations, which are defined as a worsening of clinical symptoms. Asthma exacerbations are a major cause of hospitalisation and occur in all asthmatic patients regardless of disease severity. Although mild-to-moderate asthma can generally be well-controlled with glucocorticoid (GC) treatment, exacerbations are often difficult to treat and new effective approaches are needed. Viral respiratory infections, such as respiratory syncytial virus (RSV), are associated with exacerbations in patients with pre-existing asthma. Although allergic asthma is critically regulated by increased CD4+ T-helper (Th) type 2 (Th2) responses and type 2 innate lymphoid cells (ILC2s), viral infections are thought to exacerbate asthma by enhancing allergic inflammation and/or through activation of innate immune responses. Clinical studies have identified a complex range of immune responses during viral-induced exacerbations involving Th2, Th1 and Th17 responses, and activation of host innate immunity including macrophages. However, the disease mechanisms and the role of innate immune responses in particular, which underlie viral-induced exacerbations remain poorly understood. The aim of this PhD project was to establish a mouse model of RSV-induced exacerbations, which presents hallmark features of viral-induced exacerbations in humans. This model was then used to investigate the immunological mechanisms underpinning disease, and to identify new potential approaches for treatment. Chapter 2 describes the development and characterisation of our RSV-induced exacerbation model of AHR and airway inflammation in a mouse model of pre-existing allergic airways disease (AAD). Exacerbation was associated with activation of innate host immune responses. Notably, exacerbation only occurred on the background of AAD, indicating the importance of an underlying type 2 environment for pathogenesis. Further, RSV-induced exacerbation failed to respond to GC treatment. In this study, key functional roles for tumour necrosis factor-alpha (TNFα), monocyte chemoattractant protein (MCP)-1 and pulmonary macrophages in exacerbation were demonstrated through intervention studies. Further, increased TNFα and MCP-1 expression was observed in neutrophilic asthmatic patients, a subpopulation that often poorly respond to GC treatment. Chapter 3 investigated the role of the pro-inflammatory cytokines interferon-gamma (IFN-γ) and interleukin (IL)-27 as key regulators in the model of RSV-induced steroid-resistant exacerbation. RSV-induced exacerbation increased expression of IFN-γ and IL-27, which was resistant to GC treatment. Neutralisation of either IFN-γ or IL-27 completely suppressed RSV-induced AHR. This study further highlighted the role of these molecules in conjunction with macrophages in the induction of RSV-induced exacerbation. In Chapter 4, the effectiveness of a new anti-inflammatory bromodomain and extra terminal (BET) inhibitor (I-BET) was assessed for the suppression of steroid-resistant AHR. Two steroid-resistant airways disease models; a previously-described short-term model induced by IFN-γ and lipopolysaccharide (LPS) administration to the lung (two factors linked to steroid-resistant asthma) and our RSV-induced exacerbation model (Chapter 2) were used. I-BET treatment effectively suppressed AHR and airway inflammation in both models, by inhibiting the activation of pulmonary macrophages. These findings suggest that inhibition of BET proteins may be a novel therapeutic pathway to treat asthma exacerbations, by targeting macrophages. Thus these investigations indicate that in the context of underlying pre-existing allergic airways inflammation (found in asthma), RSV infection stimulates innate immune responses, increasing inflammation and AHR. In particular, key roles for TNFα, MCP-1, IFN-γ, IL-27 and pulmonary macrophages in the pathogenesis of RSV-induced exacerbation were demonstrated. Further, the new anti-inflammatory reagent, I-BET, was shown to significantly suppress all key features of RSV-induced steroid-resistant exacerbation (e.g inflammation and AHR) and IFN-γ/LPS-induced steroid-resistant AHR. These observations provide evidence for an important role of BET proteins in the regulation of steroid-resistant AHR and airway inflammation. Therefore, these studies provide evidence that targeting innate immune activation could be a therapeutic approach for the treatment of viral-induced asthma exacerbation.
- Subject
- asthma exacerbation; respiratory syncytial virus; steroid resistance; bromodomain and extra terminal protein
- Identifier
- http://hdl.handle.net/1959.13/1337694
- Identifier
- uon:27889
- Rights
- Copyright 2017 Thi Hiep Nguyen
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 4 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 668 KB | Adobe Acrobat PDF | View Details Download |