The Role of Competitive Glycosaminoglycan Binding in Determining the Inflammatory Profile of the Cystic Fibrosis Airway
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 ex vivo and in vitro was investigated.
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.
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.
First SupervisorDr E.P. Reeves
Second SupervisorProfessor N.G. McElvaney
CommentsA thesis submitted for the degree of Doctor of Medicine from the Royal College of Surgeons in Ireland in 2018.
Published CitationWilliamson 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.
- Doctor of Medicine (MD)