Cystic fibrosis (CF) is the most common fatal inherited single gene defect in Caucasian populations. CF lung disease is characterised by infection, inflammation and progressive lung destruction. Lung inflammation is measurable in CF patients even with early disease. Gene therapy offers a theoretical cure for CF lung disease, with large clinical trials now being planned. There is not only a clear need for the development of new therapies in CF but also the means to measure the success of these therapies. One possible approach is to measure biomarkers of airway inflammation non-invasively (in sputum or serum). In this thesis I have employed a number of techniques to measure potential biomarkers in sputum and blood in both cross sectional and serial samples following treatment. Sputum was collected from patients with CF and a number of control groups including Asthma, Bronchiectasis, COPD and healthy controls. SELDI-TOF mass spectrometry was utilised to identify candidate protein biomarkers in sputum. Candidate biomarkers were then identified and compared to established biomarkers by ELISA in sputum. Emission spectroscopy was used to measure metal ions as non-protein biomarkers in sputum. SELDI TOF, ELISA and optical spectroscopy were used to measure biomarkers in CF sputum before and after exacerbation treatment. Calprotectin was also measured in serum before and after exacerbation. SELDI TOF identified calprotectin as a marker of CF lung disease, which highly discriminated CF from control. This could also be measured by ELISA and compared favourably to other inflammatory markers such as Interleukin-8 (IL-8). Emission spectroscopy identified sputum zinc and iron as discriminatory markers of CF. Sputum calprotectin and zinc levels changed significantly following treatment of CF exacerbation. Serum calprotectin also changed significantly and could predict future outcome in these patients. In this thesis I demonstrate the discover}' and application of novel biomarkers of CF lung inflammation. I describe calprotectin (sputum and serum) as useful in the monitoring of exacerbation therapy, with similar findings being displayed for sputum zinc. Further work is now required to fully validate these findings for translation into clinically useful tools.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:726433 |
| Date | January 2010 |
| Creators | Gray, Robert Donald |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/24641 |
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