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Title: Protease-antiprotease imbalance in cystic fibrosis
Author: Dunlevy, Fiona Kathleen Carol
ISNI:       0000 0001 3435 397X
Awarding Body: Queen's University of Belfast
Current Institution: Queen's University Belfast
Date of Award: 2008
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Affects over 8000 patients In the UK. Persistent neutrophilic inflammation is associated with high levels of airway NE. DX-890 is a smallprotein inhibitor ofNE developed by Dyax, USA for use in CF. This project investigated the ex-vivo effects ofDX-890 on human sputum, neutrophils and epithelial cells, to help determine the potential ofDX-890 as a drug for CF. The Ki ofDX-890 was measured to be 11.12 pM. ICso values measured in pure NE and CF sol were similar, demonstrating that DX-890 retained activity in CF sol. Thickened dehydrated CF mucus may prevent access ofDX-890 to NE and reduce efficacy ill vivo. It was hypothesised that, by reducing stickiness of sputum with DNase or surfactant, DX-890 activity would be enhanced. DX-890 inhibited significantly more NE when sputum was pre-treated with surfactant ill vitro. DX-890 reduced release of active NE from fMLP-activated neutrophils and it was found that DX-890 also inhibits NE inside the neutrophil. DX-890 significantly reduced transmigration of neutrophils across a monolayer ofepithelial cells in response to fMLP, implicating NE activity in the process of transmigration. Nasal epithelial cells from CF and non-CF participants were grown in a monolayer and release of the proinflammatory mediator IL-8 was measured. DX-890 prevented NE induced IL-8 release and also IL-8 release induced by CF sol. In conclusion, inhibition ofNE with DX-890 may reduce airway inflammation by minimising production of IL-8 from epithelial cells, and release of active NE from neutrophils. DX-890 efficacy in whole sputum may be enhanced by co-treatment with surfactant. Used in conjunction with current CF therapies such as antibiotics and physiotherapy, DX-890 may help prevent lung damage and prolong life by reducing airway
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available