Acute Respiratory Distress Syndrome (ARDS) is characterised by dysregulated inflammation within the lungs, which can severely compromise pulmonary architecture and function. Despite intensive efforts to develop therapies for ARDS, there are no curative pharmacological interventions at present. Instead, management of ARDS is primarily supportive and the syndrome is associated with substantial mortality, morbidity and healthcare expenditure. In pursuit of an effective ARDS therapy, this thesis explored the potential application of a novel sialic acid-functionalised nanoparticle (SNP). This nanoplatform was designed to actively target sialic acid-binding immunoglobulin-like lectin (Siglec) receptors expressed on monocytes and macrophages, which exert a fundamental role in the negative regulation of inflammatory responses. Initially, SNP were evaluated in a murine model of lipopolysaccharide (LPS)-induced lung injury, where promising outcomes were observed. SNP attenuated several lung injury parameters in this model, including neutrophilia and pro-inflammatory cytokine levels in the pronchoalveolar lavage fluid (BALF), amongst others. Crucially, the translational efficacy of SNP was confirmed in human models of LPS-induced inflammation. SNP inhibited pro-inflammatory cytokine production in cultures of primary human cells implicated in ARDS, whilst concurrently enhancing levels of antiinflammatory interleukin (IL)-10. The protective effects of SNP were also evident in whole human lungs injured with LPS ex vivo, where reductions in pulmonary oedema and BALF cellularity were observed. Collectively, these findings highlight the potential of SNP to combat the inflammatory component of ARDS and fulfill the clinical need for an effective therapy.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:680123 |
| Date | January 2015 |
| Creators | Greene, Michelle Kathleen |
| Publisher | Queen's University Belfast |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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