- Title
- Role of mechanical forces in asthma pathogenesis
- Creator
- Veerati, Punnam Chander
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2019
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Asthma is characterised by bronchoconstriction which leads to clinical symptoms and generates mechanical forces within the airway. During virally induced asthma exacerbations, bronchoconstriction and viral infection occur simultaneously; these factors may interact in the airway leading to the apparent innate immune deficiencies demonstrated in some asthmatics. This lead to our overarching hypothesis that “airway compressive forces suppress innate immunity following viral infection in asthmatics”. To investigate this in in-vitro using a full experimental time course, there was a requirement for high cell numbers from individual patients with respiratory diseases such as asthma. Initially, we performed cell line optimisation to try to establish air-liquid interface (ALI) cultures. Later we used a conditionally reprogrammed (CR) technique on primary bronchial epithelial cells (pBECs) to proliferate indefinitely for extended passages and then used those at ALI. In order to investigate the effects of apical compression on cells during viral infection, we wished to use a model which as closely as possible mimicked human airway infection in-vivo. Therefore we developed a physiologically relevant RV1B infection model and demonstrated for the first time that ultra-low multiplicity of infection induces delayed innate immune responses from cells obtained from asthma and COPD donors in comparison to healthy controls. Here we used cells obtained from COPD donors along with asthma to investigate anti-viral responses; as previously it was shown that the anti-viral responses from COPD cells were also altered. In order to investigate the effect of bronchoconstriction on anti-viral responses, we exposed pBECs obtained from asthmatic donors, grown at ALI to apical compressive stress mimicking bronchoconstriction along with physiologically relevant RV infection. We examined the effect of mechanical forces occurring prior to infection (mimicking poorly controlled asthma), or during viral infection (mimicking virally induced asthma exacerbation). We demonstrate that apical compression suppresses innate immune responses from asthmatic pBECs under these conditions. Our data may explain why the patients with less well-controlled asthmatics appear more vulnerable to viral infection and why some asthmatics appear to have deficient Interferon (IFN) responses to natural infections.
- Subject
- asthma; bronchoconstriction; mechanical forces; apical compression; rhinovirus; innate immunity
- Identifier
- http://hdl.handle.net/1959.13/1404616
- Identifier
- uon:35372
- Rights
- Copyright 2019 Punnam Chander Veerati
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 9 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 414 KB | Adobe Acrobat PDF | View Details Download |