- Title
- Investigating asthma-COPD overlap using mouse models
- Creator
- Tu, Xiaofan
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2022
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Background: Asthma and chronic obstructive pulmonary disease (COPD) are two of the most common chronic respiratory diseases that impart significant disease burden. In recent years, the co-existence of both asthma and COPD features in the same individual, termed asthma-COPD overlap (ACO), has garnered significant interest as these patients have been poorly studied in the past but often present with increased disease severity. Hypothesis and aims: We hypothesised that developing a novel mouse model of ACO using clinically relevant stimuli would provide valuable insights into the pathogenesis of ACO as well as help identify potential new therapies. Therefore, we aimed to characterise the phenotypic and transcriptomic features of experimental ACO induced by chronic house dust mite (HDM) antigen and cigarette smoke (CS) exposure and compare those with experimental asthma and COPD. In addition, we aimed to identify and validate novel molecular targets that may lead to new therapies for chronic respiratory diseases. Methods: Female BALB/c mice were chronically exposed to HDM for 11 weeks to induce experimental asthma, CS for 8 weeks to induce experimental COPD, or both concurrently to induce experimental ACO. Phenotypic characterisation was conducted by assessing airway and parenchymal inflammation and remodelling as well as lung function. RNA-sequencing was performed on separate airway and parenchymal lung tissues to assess transcriptional changes. Potential therapeutic targets were identified through network and differential gene expression analysis and were validated using novel pharmacological inhibitors in both short- and long-term models of airway disease. Results: Experimental ACO recapitulated features of both asthma and COPD and demonstrated mixed pulmonary inflammation but greater airway hyperresponsiveness (AHR) that was steroid insensitive. Transcriptomic analysis revealed greater changes associated with chronic HDM exposure than CS exposure and identified common as well as unique transcriptional changes between experimental asthma, COPD, and ACO. In addition, key transcription factors governing dysregulated gene clusters were identified across all three experimental groups, including overexpression of the transcription factor Spi1. Pharmacological inhibition of SPI1 protein using novel small molecule inhibitors resulted in reduced airway remodelling in short-term allergic airway disease (AAD) as well as reduced AHR in both short-term AAD and experimental ACO. Conclusion: A new experimental model of ACO featuring chronic dual exposures to HDM and CS recreated phenotypes observed in patients with ACO and revealed novel disease mechanisms that are amenable to therapy.
- Subject
- asthma; COPD; asthma-COPD overlap; ACO; mouse model; RNA-Seq; chronic respiratory disease
- Identifier
- http://hdl.handle.net/1959.13/1505051
- Identifier
- uon:55612
- Rights
- Copyright 2022 Xiaofan Tu
- 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 | 276 KB | Adobe Acrobat PDF | View Details Download |