- Title
- Oxidative stress impairs mitochondrial function in healthy and asthmatic primary bronchial epithelial cells
- Creator
- Fathi Aghdam, Faezeh
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2015
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Asthma is associated with increased reactive oxidant species (ROS) in the airways which can lead to oxidative stress. A combination of several factors, such as viral infection, exposure to tobacco smoke or allergens may contribute to asthma exacerbations in the absence of effective type I and type III IFN responses. Rhinovirus infections (RVs) are associated with the majority of acute asthma exacerbations in children and adults. Mitochondria play a significant role in antiviral defence, via induction of innate immune responses through melanoma differentiation-associated gene 5 (MDA5) and mitochondrial antiviral signalling protein (MAVS) which is important for the downstream activation of type I and type III IFNs in epithelial cells. Our aims were to compare mitochondrial function and antiviral responses to RV infection in pBECs in asthmatics and healthy controls (HC) and to see whether the oxidative damage to the mitochondria can be reversed using lycopene and carnitine. Exposure of pBECs to CSE/H₂O₂resulted in mitochondrial damage; with impaired mitochondrial membrane integrity and the co-localisation of MAVS, MDA5 and mitochondria, increased expression of mTFs, release of cytochrome-c and ATP from mitochondria which was greater in asthmatic pBECs. RV+CSE/H₂O₂further increased mTFs and ATP release which again was exaggerated in asthmatics compared to HC. CSE and H₂O₂ had no effect on MAVS cleavage or the protein expression of MDA5, pIRF3, TBK1 and IKKɛ in both groups. Asthmatics demonstrated an impaired IFN response with, reduced CXCL-10 and IFN- λ and an increase in CXCL-8 and IL-6 release compared to HC. Also, CSE and H₂O₂led to increased RV replication which was greater in asthmatics compared to HC. Lycopene and carnitine restored mitochondrial membrane integrity and the co-localisation between MAVS, MDA5 and mitochondria. They decreased inflammation by a marked reduction in the release of CXCL-8 and IL-6. In addition, they reduced RV replication, but did not restore CXCL-10 and IFN- λ responses.
- Subject
- asthma; reactive oxidant species; oxidative stress; mitochondria
- Identifier
- http://hdl.handle.net/1959.13/1296499
- Identifier
- uon:19268
- Rights
- Copyright 2015 Faezeh Fathi Aghdam
- Language
- eng
- Full Text
- Hits: 1525
- Visitors: 2720
- Downloads: 1101
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Abstract | 605 KB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Thesis | 4 MB | Adobe Acrobat PDF | View Details Download |