Cystic fibrosis (CF) and Primary Ciliary Dyskinesia (PCD) are chronic suppurative lung diseases (CSLD). CF is characterised by inherited mutations affecting the cystic fibrosis transmembrane regulator (CFTR) protein, which is thought to be normal in PCD, however the role of CFTR in
disease is incompletely understood. This thesis investigates the relationship between CFTR, inflammation and airway health, firstly in the context of the CF gene therapy Multidose trial followed by contrasting CF, PCD and control patients.
The first study explored the relationship between lower airway potential difference (LAPD) measurements performed in the Multidose trial as a measure of CFTR function, and physiological, radiographic and inflammatory markers of disease severity. At baseline, FEV1 correlated with basal LAPD measurements, however not between restored chloride secretion and change in airway disease following treatment; implicating the role of sodium transport, not chloride in disease
pathogenesis. As no direct correlation was seen, I went on to explore an alternative theory that a bi-directional relationship exists between CFTR and inflammation; CFTR dysfunction triggers a hyper-inflammatory state and inflammation causes secondary CFTR dysfunction. Cell cultures were cultivated from the nasal epithelium of patients with CF, PCD and controls. Both
at baseline and following stimulation with common respiratory pathogens, the levels of
inflammatory mediators in the supernatant from each group of cells were comparable. The numbers involved with this study were small, however did not indicate that CF cells cultured in these conditions (in vitro) were hyper-inflammatory.
The final study explored in vivo whether inflammation causes secondary CFTR dysfunction. Nasal potential difference (NPD) measurements were compared with localised levels of inflammation in
subjects with CF, PCD and controls. PCD traces showed reduced chloride secretion, however it was not possible to differentiate secondary CFTR dysfunction from damage to epithelial cell integrity. Elevated levels of inflammatory mediators were detected in PCD nasal fluid, however the results were variable and these levels did not correlate with NPD measurements of ion channel
function.
These studies did not support the hypothesis that there is a direct relationship between CFTR function and airway disease, that in vitro CF cells are hyperinflammatory, or in vivo that
inflammation leads to secondary CFTR dysfunction. The experiments performed in this thesis provide a basis for future work exploring this relationship, and may help guide future trials for novel therapies in CF.