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The Role of Competitive Glycosaminoglycan Binding in Determining the Inflammatory Profile of the Cystic Fibrosis Airway
Williamson, Michael
<p>Lung disease of cystic fibrosis (CF) is aggravated by intense airway inflammation with high concentrations of chemotactic interleukin (IL)-8 protected from proteolytic degradation by binding to glycosaminoglycans (GAGs). In contrast IL-18 is mostly absent from the CF airways. The aim of this project was to compare these two pro-inflammatory cytokines for their relative stability, activity, and interaction with GAGs. Further, the ability of increased hypertonicity, induced by hypertonic saline (HTS) treatment, to alter IL-8 interaction with GAGs both <em>ex vivo</em> and <em>in vitro</em> was investigated.</p> <p>Raised levels of IL-8 and reduced concentrations of IL-18 were detected in airway secretions from CF individuals. Pro- and mature forms of IL-18 were expressed and produced normally by CF epithelial cells and monocytes; however, a marked competition between IL-8 and IL-18 for binding to GAGs was demonstrated. A pronounced loss of IL-18 binding occurred in the presence of IL-8, with displaced IL-18 rendered susceptible to proteolysis by neutrophil elastase. In turn, GAG lysis in CF BALF displaced bound IL-8, allowing IL-8 proteolytic degradation. High sodium concentrations also liberate IL-8 in CF BALF and in CF sputum from patients receiving nebulised HTS, resulting in IL-8 degradation and decreased chemotactic efficiency.</p> <p>In conclusion, the potential of GAGs to influence the chemokine profile of the CF lung by stabilizing specific inflammatory mediators has been demonstrated. Competition from IL-8 determines the fate of other inflammatory molecules, such as IL-18, within the CF lung inflammatory milieu. A novel mechanism has been identified highlighting the potential of nebulised HTS to decrease neutrophil chemotaxis, facilitating resolution of inflammation.</p> <p>A thesis submitted for the degree of Doctor of Medicine from the Royal College of Surgeons in Ireland in 2018.</p>
Keyword(s): Cystic Fibrosis; Interleukins; Interleukin-8; Interleukin-18; Cytokines; Medicine and Health Sciences; Pulmonology; Translational Medical Research
Publication Date:
Type: Doctoral thesis
Peer-Reviewed: Yes
Institution: Royal College of Surgeons in Ireland
Citation(s): Williamson M. The role of competitive glycosaminoglycan binding in determining the inflammatory profile of the cystic fibrosis airways [MD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2018.
Supervisor(s): Dr E.P. Reeves
Professor N.G. McElvaney
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First Indexed: 2018-12-15 07:21:39 Last Updated: 2018-12-15 07:21:39