- Title
- Elucidating the mechanisms of steroid-resistant asthma
- Creator
- Pinkerton , James
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2018
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Severe, steroid-resistant (SSR) asthma is of considerable clinical and economic significance as affected individuals do not respond to mainstay corticosteroid therapies. Patients with SSR asthma experience more frequent exacerbations of disease, are more likely to require hospitalisation and have a poor quality of life. Improved therapies are urgently required for SSR asthma, however, progress in this area has been hampered by a lack of understanding of the pathological processes that underpin disease. The major obstacle to understanding the processes that drive SSR asthma is that there are several subsets of the disease characterised by different inflammatory and immunological phenotypes. This heterogeneity disease makes pinpointing the key processes that underpin disease extremely difficult in humans. To help understand the mechanisms that underpin SSR asthma, we have developed three unique infection-induced models of SSR asthma. As part of my thesis, I have also developed a high fat diet-induced, obesity-associated SSR asthma. Together, all four models recapitulate the key features of a number of different subsets/clusters of SSR asthma in the clinic and represent useful tools to understand subset-specific and universal factors/processes that underpin of disease and test novel therapies that target the factors/processes identified. The overarching aim of my PhD is to utilise these models to elucidate novel mechanisms that may underpin SSR asthma and to determine whether targeting these mechanisms with therapeutic interventions can suppress disease, where steroids are not effective. My PhD was divided into three major aims that have focused on discovering novel factors associated with disease and assessing the roles played by known associative factors potentially drive steroid resistance. Firstly, I conducted array analyses on whole lung tissue from our three models of infection-induced SSR asthma, that represent different inflammatory and immune subsets observed in the clinic, to identify factors that are universally dysregulated in disease. I identified 11 universally dysregulated genes, most of which have not been previously recognised in SSR asthma (chapter 2). I then showed the functional role that one of these factors may being playing in driving SSR asthma (chapter 2). Secondly, I have identified dysregulated antioxidant responses as playing a critical role in our Chlamydia-induced model of SSR asthma and show that restoration of antioxidant responses may be a beneficial adjunct therapy for steroid-resistant disease (chapter 3). Lastly, I have developed a new murine model of high fat diet (HFD)-induced obesity that induces SSR allergic airways disease (AAD) (chapter 4). I used this model to identify a previously unrecognised role for HFD/obesity-induced, NLRP3 inflammasome-mediated responses in the lung the development of steroid-resistant airways hyper-responsiveness (AHR). I also show that HFD/obesity induced NLRP3 inflammasome responses in the lung may be therapeutically targeted for the treatment of HFD/obesity-associated, steroid-resistant AHR. Together the findings from my PhD studies inform new mechanisms and pathways that may underpin SSR asthma in the clinical setting and highlight potential therapeutic targets and strategies for the treatment of disease. The development of a representative obesity-induced model of SSR asthma will be a useful tool for future studies that aim to identify mechanisms and treatment strategies for obese SSR asthmatics.
- Subject
- asthma; severe asthma; steroid resistance; infection; obesity
- Identifier
- http://hdl.handle.net/1959.13/1383707
- Identifier
- uon:31975
- Rights
- Copyright 2018 James Pinkerton
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 8 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 146 KB | Adobe Acrobat PDF | View Details Download |