Secretory leucoprotease inhibitor (SLPI) has multifaceted roles in protecting tissues from the damaging effects of inflammation. In addition to its well characterised role as a protease inhibitor, SLPI has been shown to have anti-inflammatory and anti-microbial properties. The therapeutic potential for SLPI as an anti-inflammatory treatment has previously been assessed in chronic inflammatory conditions and has shown promising results in a clinical trial with cystic fibrosis (CF) patients. There is evidence to suggest that SLPI can also inhibit acute inflammation; however the administration of exogenous SLPI as a therapy during the acute inflammatory response has never been investigated. The work presented in this thesis establishes recombinant human SLPI (rhSLPI) as a wide-acting anti-inflammatory following both systemic and pulmonary inflammation induced by bacterial cell surface components. Additionally, rhSLPI was able to reduce a number of inflammatory parameters following pulmonary Pseudomonas aeruginosa infection; however it had no effect on bacterial burden. It was noted that despite reductions in known pro-inflammatory markers, IL-17 was increased following rhSLPI treatment. This IL-17 was shown to be from double negative (ON) T cells, which have been previously reported to play a protective role following pulmonary infection. The importance of SLPI as an inflammatory regulator is established through the increased susceptibility of SLPI knockout (KO) mice to LPS-induced lung inflammation as well as Pseudomonas and Staphylococcus pulmonary infection. Together this gives evidence that SLPI modulates the acute inflammatory response. It should therefore be considered as an anti-inflammatory therapeutic for acute sterile conditions, such as pancreatitis, or acute infections such as that seen in acute respiratory distress syndrome (AROS) patients where it could be combined with antibiotics.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:677459 |
| Date | January 2015 |
| Creators | Osbourn, Megan |
| Publisher | Queen's University Belfast |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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