Obligate anaerobic bacteria such as Prevotella are present in large numbers in the lower airways of Cystic Fibrosis (CF) patients. However, their contribution to the development and/or perpetuation of bronchiectasis is unknown. In CF, unopposed Matrix Metalloproteinase (MMP) activity drives loss of extracellular matrix proteins, leading to loss of elastic tissue and cartilage destruction and its high activity reported in CF sputum inversely correlates with lung function (FEV1). In our lab it has been previously shown that Pseudomonas aeruginosa (PA01) drives unopposed production of MMP-9 in infected leukocytes and can further drive unopposed MMP-9 by non CF and CF cell lines regulated by mitogen activated protein kinase (MAPK) dependent mechanisms via an inflammatory-epithelial cell network. PA01 also degraded MMP-9's natural in vivo inhibitor, Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) in vitro. Prevotella have been implicated in driving net-MMP-dependent proteolytic activity and tissue destruction in periodontal disease, however their role in CF has yet to be determined. Direct Prevotella infection of mononuclear cells, drove heightened pr?-inflammatory responses coupled with an increase in MMP-9 and TIMP-1. These effects were also observed when Prevotella-infected mononuclear conditioned media was used to stimulate epithelial cell lines, CF and non-CF via an inflammatory-epithelial cell network. Direct mononuclear infection of Prevotella was shown to activate MAPK and NF-KB signalling pathways. In addition Prevotella were shown to destroy TIMP-1 protein through secretion of a cysteine protease, which may suggest an indirect contribution to net proteolytic activity. In summary, Prevotella may contribute to the pro-inflammatory cascade in CF but may not directly drive net MMP-dependent proteolytic activity through cellular mechanisms. However it may favour a proteolytic phenotype by the degradation of TIMP-1, indirectly contributing to tissue destruction in CF.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:680071 |
| Date | January 2015 |
| Creators | Jackson, Megan |
| Publisher | Queen's University Belfast |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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