- Title
- Investigating aberrant inflammatory signalling in asthma
- Creator
- Niessen, Natalie Margret
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2021
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Asthma is a chronic obstructive airway disease that is estimated to effect 340 million people worldwide. The underlying inflammation of the airways is heterogeneous and different asthma inflammatory phenotypes have been identified, that are associated with varying responses to treatment. Approximately 15 % of those with asthma feature neutrophilic airway inflammation, defined by elevated sputum neutrophils, that is associated with corticosteroid resistance and more severe disease. As yet, suitable treatment for neutrophilic asthma is lacking and a better understanding of the pathophysiological changes underlying this inflammatory phenotype is necessary in order to identify novel therapeutic targets. This thesis reveals novel aspects of neutrophilic asthma, namely, altered airway immune cell trafficking and dysregulation of the TNF signalling pathway. In chapter 3 I demonstrate that neutrophilic asthma is associated with increased recruitment of monocytes to the airways, while airway macrophages appear to be reduced. Dysregulation of the monocyte/macrophage lineage could relate to an altered inflammatory response, as these two cell types may execute distinct functions in tissue homeostasis and inflammation. Chapter 4 investigates the relative abundance of the inflammatory markers TNF, TNFR1 and TNFR2 in the circulation and the airways. I demonstrate that neutrophilic asthma is associated with increased soluble receptor levels in the airways, whereas membrane-bound TNF markers do not differ across asthma inflammatory phenotypes or in comparison to non-asthma controls. These alterations could relate to aberrant inflammatory signalling and/or impaired inflammatory resolution and thus contribute to airway inflammation in neutrophilic asthma. In chapter 5, I show that increased soluble TNF receptors in both circulation and the airways are associated with clinical features of asthma, such as reduced lung function, more frequent exacerbation and more severe asthma, suggesting that dysregulated TNF signalling contributes to worse asthma outcomes. I further demonstrate that long-term low-dose administration of azithromycin significantly reduces soluble TNF marker levels. My results imply that the mechanisms of action of AZM could be a combination of both general and specific mechanisms and potentially involve anti-inflammatory and anti-bacterial properties of the macrolide. My observations in neutrophilic asthma prompt new hypotheses that require further investigation and validation in mechanistic studies.
- Subject
- asthma; neutrophilic asthma; sputum; whole blood; macrolide; azithromycin; thesis by publication; severe asthma; monocytes; monocyte subsets; macrophages; neutrophils; TNF signalling; flow cytometry; ELISA
- Identifier
- http://hdl.handle.net/1959.13/1429947
- Identifier
- uon:38782
- Rights
- Copyright 2021 Natalie Margret Niessen
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 12 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 385 KB | Adobe Acrobat PDF | View Details Download |