- Title
- Dietary fatty acids and innate immune responses in primary human lung cells
- Creator
- Rutting, Sandra
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2019
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Obesity is a major risk factor for asthma development, and furthermore, the obese asthma phenotype is characterised by an increased risk of severe exacerbations, increased systemic inflammation, greater asthma severity, poorer asthma control and quality of life, and a lack of atopy with neutrophilic inflammation being specifically reported in obese women. However, the mechanisms that underpin the clinical differences between lean and obese asthma patients are still unclear. Current evidence suggests dietary fat intake to be a major factor that contributes to the more severe obese asthma phenotype, potentially by activating the innate immune system. In Chapter 2 of this thesis, I investigated the effects of different types of dietary fatty acids (ω-3 polyunsaturated fatty acids (PUFAs), ω-6 PUFAs and saturated fatty acids (SFAs)) on innate immune responses in primary human lung cells, by measuring the release of the pro-inflammatory cytokines interleukin (IL)-6 and CXCL8. The data showed that ω-6 PUFAs, but not ω-3 PUFAs or SFAs, induce robust innate immune responses and synergise with obesity-associated pro-inflammatory cytokines in primary lung mesenchymal, but not bronchial epithelial cells. This study also identified the underlying signalling pathways, thereby identifying potential therapeutic targets to treat obesity and high-fat diet-mediated inflammation. In Chapter 3, I have modelled the effects of dietary fatty acids upon infectious exacerbations of asthma in vitro. Our data showed that challenge with ω-6 PUFAs and the viral mimic PolyI:C or bacterial compound LTA leads to substantially greater pro-inflammatory cytokine release than either challenge alone in pulmonary fibroblasts and bronchial epithelial cells. In epithelial cells, SFAs combined with PolyI:C also led to greater IL-6 release. In addition, I demonstrated that the ω-6 PUFA arachidonic acid enhanced RV-induced cytokine release from primary pulmonary fibroblasts and epithelial cells. These findings suggest that during respiratory infection, increased levels of dietary ω-6 PUFAs and SFAs may contribute to and/or increase the severity of asthma exacerbations. Several studies have shown that short chain fatty acids (SCFAs), which are produced as by-products of dietary fibre metabolism by gut bacteria, have anti-inflammatory properties and therefore could potentially be used for the treatment of asthma. In Chapter 4 I investigated whether SCFAs can protect against TNFα-induced inflammation in primary human lung cells. I found that SCFAs did not suppress TNFα-induced cytokine release. On the contrary, challenge with SCFAs in combination with TNFα resulted in substantially greater pro-inflammatory cytokine release from primary lung mesenchymal cells, than challenge with TNFα alone. This study demonstrates that SCFAs generate pro-inflammatory rather than anti-inflammatory responses in lung mesenchymal cells and these effects could potentially reduce the efficacy of using SCFAs as a therapeutic strategy for asthma management. The effects of obesity and high fat diets in chronic obstructive pulmonary disease (COPD) are less extensively studied, but current evidence suggests them to be protective or less harmful compared to in asthma. Therefore, I hypothesised that cells from COPD patients are intrinsically different from cells derived from patients with other lung diseases and respond differently to dietary fatty acids. In Chapter 5 I assessed the response to dietary fatty acids upon markers of inflammation and remodelling in human lung cells from people with and without COPD. I found that cells from COPD patients had a reduced inflammatory response to ω-6 PUFAs compared to non-COPD cells. In addition, ω-6 PUFAs, but not SFAs or ω-3 PUFAs, reduced the basal deposition of extracellular matrix (ECM) proteins. Moreover, the ω-6 PUFA AA had a more substantial inhibitory effect on basal ECM-protein deposition in COPD cells compared to non-COPD cells. These findings suggest that dietary fatty acids have disease-specific effects and this could potentially explain the differential effects of high fat diets in different lung diseases. This thesis shows that dietary fatty acids enhance innate immune responses in primary human structural lung cells and suggests that increased levels of dietary fatty acids could play a role in the more severe asthma phenotype observed in obese patients. I have also delineated the underlying molecular mechanisms and thereby identified potential therapeutic targets. Importantly, these studies suggest that reducing serum fatty acids would have beneficial outcomes for obese asthmatics and that further research may enable the identification of potential therapeutic targets, which could facilitate better clinical outcomes in terms of morbidity and mortality in obese asthma.
- Subject
- asthma; COPD; obesity; dietary fatty acids; immunology; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1406475
- Identifier
- uon:35633
- Rights
- Copyright 2019 Sandra Rutting
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 17 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 370 KB | Adobe Acrobat PDF | View Details Download |