AbstractCystic fibrosis is a lethal autosomal recessive disease, caused by a defect of the cystic fibrosis transmembrane conductance regulator (CFTR), which is characterised by lung disease. However, medical advances mean the survival age is increasing and, as such, various non-pulmonary co-morbidities are modulating quality and longevity of life. For instance, cystic fibrosis-related diabetes is the most common non-respiratory consequence of cystic fibrosis, which is associated with poorer lung disease and vascular dysfunction. Furthermore, endothelial perturbation is observed in people with cystic fibrosis without dysglycaemia and may modulate aerobic exercise dysfunction. Therefore, it was hypothesised that cystic fibrosis-related dysglycaemia would impair aerobic exercise and ventilatory function, which would be associated with microvascular endothelial dysfunction and oxidative stress.
Data within this thesis demonstrated, for the first time, that the determination of maximal oxygen uptake was safe, valid and feasible amongst children, adolescents and adults with mild to severe lung disease. When utilising this protocol, it was also revealed that maximal aerobic fitness was impaired in people with cystic fibrosis-related diabetes compared to their age- and sex-matched counterparts with cystic fibrosis and normal glucose tolerance. Ventilation-perfusion mismatches were also observed in a 3rd of adults with cystic fibrosis, irrespective of their glycaemic status. Cell culture studies demonstrated that CFTR regulated inflammation, oxidative stress and cell signalling in the human lung microvasculature, which ultimately promoted optimal actin cytoskeleton formation and cell alignment in response to flow. Therefore, a loss of CFTR function could cause lung microvascular perturbation and ventilation-perfusion mismatches in vivo. Oxidative stress in cystic fibrosis is an important pathophysiological mechanism for these observations; furthermore, it was observed that biomarkers of oxidative stress were elevated in people with clinically-stable cystic fibrosis.
Together, these data provide promising rationale to study redox-based therapeutics in models of cystic fibrosis-related lung disease, dysglycaemia and endothelial dysfunction.
|Date of Award
|Zoe Saynor (Supervisor) & Jan Shute (Supervisor)