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Title: Airway remodelling in asthma
Author: Leggett, Julian James
ISNI:       0000 0001 3607 7905
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2008
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Asthma management places significant financial demands on health services. With increased understanding of the mediators involved in asthma pathophysiology more specific agents could be developed for treatment. We studied the effects of oxidant injury- on adult asthmatic cells in vitro and showed asthmatic epithelium more susceptible to oxidative stress at high concentrations of hydrogen peroxide. Cell death occurred via caspase independent apoptosis. However, at lower doses of hydrogen peroxide proliferation was observed suggesting a biphasic response. We investigated levels of Matrix Metalloproteinase-9 (MMP-9) and its inhibitor Tissue Inhibitor of Matrix Metalloproteinase-1 (TIMP-1) in the induced sputum, bronchial wash and bronchoalveolar lavage fluid (BALF) of adult asthmatics and their correlation to- their respective immunostaining in bronchial biopsies. Bronchoalveolar lavage fluid in asthmatics demonstrates significantly raised TIMP-1 levels suggesting derangement in extracellular matrix turnover. Involvement of TIMP-1 in asthma pathophysiology is further supported by the finding that TIMP-1 immunostaining correlated with markers of asthma severity. In contrast no such relationship was observed with MMP-9, suggesting an imbalance between MMP-9 and TIMP-1 may be important in remodelling 'of the airway in asthma. Increased Epithelial Growth Factor (EGF) staining was observed within the basal • controls. However, no difference in EGF levels between asthmatics and controls in epithelial layer and in submucosal macrophages of asthmatics compared to either BALF or bronchial wash was found. In the 'asthmatic subjects studied response. In conclusion, this data suggests the epithelial response to increased Epithelial Growth Factor Receptor (EGFR) correlated positively with PC20 suggesting that in mild asthma increased EGFR represents an appropriate repair EGFR expression in mild asthma appears appropriate. In summary, asthmatic bronchial epithelium demonstrates an altered response to oxidative stress. This thesis further supports the evidence for abnormal epithelial cell response in asthma to oxidative stress and an imbalance in matrix turnover in the asthmatic airway.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available