- Title
- Inflammatory mechanisms in non-eosinophilic asthma
- Creator
- Simpson, Jodie Louise
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2005
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Asthma is defined as a 'chronic inflammatory disorder of the airways, which involves many cells and cellular elements". Eosinophilic airway responses have been well characterised in asthma, and recently non-eosinophilic forms of asthma have been identified. The non-eosinophilic asthma phenotype is characterised by clinical symptoms of asthma and airway hyperresponsiveness occurring in the absence of raised sputum eosinophils. The non-eosinophilic pattern of inflammation has been reported across whole spectrum of asthma severity including mild asthma, persistent asthma and severe refractory asthma. The aim of this thesis was to investigate the characteristics and inflammatory mechanisms of non-eosinophilic asthma. The recognition of non-eosinophilic asthma using induced sputum eosinophil counts was examined. The role of proteolytic enzymes and innate immune activation as potential mechanisms of non-eosinophilic asthma were also examined in subjects with stable persistent symptomatic asthma treated with inhaled corticosteroids and healthy controls. A definition of non-eosinophilic asthma based upon a normal sputum eosinophil proportion was found to be reproducible. This was a heterogeneous inflammatory phenotype containing a group with increased neutrophils (neutrophilic asthma) and a group with normal levels of neutrophils and eosinophils termed paucigranulocytic asthma. Eosinophilic asthma was characterised by the presence of high levels of active matrix metalloproteinase-9 and low levels of neutrophil elastase. Neutrophilic asthma was characterised by high levels of neutrophil elastase and almost no active matrix metalloproteinase-9. Subjects with neutrophilic asthma also had evidence of chronic bacterial colonisation of the airways, high levels of airway endotoxin and innate immune activation with increased expression of the toll-like receptors 2 and 4 and increased surfactant protein A in sputum. Airway inflammation is heterogenous and can be classified into phenotypes based upon abnormal levels of sputum neutrophils and eosinophils. More than 50% of symptomatic persistent asthma is non-eosinophilic in nature, with more than 20% of these subjects having a neutrophilic airway inflammation and the remainder exhibiting a paucigranulocytic asthma. Innate immune activation is an important inflammatory mechanism in neutrophilic asthma, which may explain the increased expression of pro-inflammatory cytokines and proteolytic enzymes in neutrophilic asthma. Over 30% of subjects with persistent asthma have a persistent eosinophilia despite receiving high doses of inhaled corticosteroids. The findings of this thesis have important implications for the management, treatment and monitoring of asthma and support the inclusion of a measure of airway inflammation in the clinical assessment of asthma to guide therapy and further investigation into airway disease.
- Subject
- chronic inflammatory disorder; eosinophilic airway responses; treatment; airway inflammation
- Identifier
- http://hdl.handle.net/1959.13/1418343
- Identifier
- uon:37335
- Rights
- Copyright 2005 Jodie Louise Simpson
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 122 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 10 MB | Adobe Acrobat PDF | View Details Download |