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Title: The role of matrix metalloproteinases in cystic fibrosis
Author: Moffett, J. F.
ISNI:       0000 0004 2742 0953
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2013
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Cystic fibrosis (CF) lung disease is characterised by progressive destruction and dilatation of the airways. This occurs in the setting of chronic infection, particularly with Pseudomonas aeruginosa (Pa), and is associated with loss of elastin and cartilage, with progressive submucosal fibrosis. Matrix Metalloproteinases (MMPs) can degrade all components of the extracellular matrix, and are inhibited by the Tissue Inhibitors of Metalloproteinases (TIMPs). High MMP-9 activity has been identified in CF sputum, and correlates inversely with lung function (FEV1). The source and regulation of MMP-9 in CF is unknown. Direct Pa infection of epithelial cells resulted in destruction of TIMP-1, the major inhibitor of MMP-9. Pa infection of inflammatory cells" neutrophils, monocytes and monocyte derived macrophages (MDMs); resulted in an unopposed increase in MMP-9. Conditioned media from Pa infected neutrophils (coNPa), monocytes (coMPa) and MDMs (coMDMPa) drove further secretion of MMP-9 from epithelial cells. This was shown to be regulatecl by Mitogen activated protein kinase (MAPK) pathways. The functional, matrix degrading effects of MMPs produced following conditioned media stimulation were examined and revealed that stimulated epithelial cells were able to invade through a matrigel membrane and drive an invasive phenotype, potentially characterising the involvement of MMPs in extracellular matrix breakdown in CF. Further, MMP-9 secretion in conjunction with cytokines and growth factors found in the CF airway, acted on epithelial cells resulting in loss of epithelial cell contact with basement membrane and subsequent invasion of epithelium into the mesenchyme- a process known as Epithelial to mesenchymal transition (EMT). In summary, infiltrating leukocytes and the lung parenchyma are potential sources of excessive MMP-9 activity in CF, and may contribute to the airway destruction that occurs in response to Pa infection.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available