Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. In COPD, an imbalance is believed to exist between the activities of neutrophil serine proteinases (NSPs) such as neutrophil elastase (NE) and proteinase 3 (PR3), and their endogenous inhibitors such as alpha-1-antitrypsin (A1AT). Hence, a deficiency of A1AT predisposes to the development of COPD. Following their release from neutrophils, NSPs may bind to local inhibitors depending on their concentrations and affinities, to substrate such as lung elastin or to the neutrophil cell membrane where they remain active. This work has demonstrated that; NSPs bound to the proteinase “inhibitor” alpha-2-macroglobulin (A2M) remain active, and A2M:NE complexes are able to degrade elastin in vitro; NE bound to elastin is poorly inhibited by A1AT; and PR3 binding to the neutrophil cell membrane is greater when the local concentration of A1AT is reduced. The role of PR3 has not previously been studied in detail. However, PR3 activity was found to be present in sputum from clinically stable subjects with COPD or A1AT deficiency and was greater than NE activity. Hence, PR3 is likely to be important in the pathogenesis of COPD and could potentially be a target for therapeutic inhibitors.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:577827 |
| Date | January 2013 |
| Creators | Sinden, Nicola Jane |
| Publisher | University of Birmingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://etheses.bham.ac.uk//id/eprint/4404/ |
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