The Pathophysiology of Cystic Fibrosis Lung Disease

Cystic fibrosis (CF) lung disease is characterized by recurrent cycles of infection and inflammation, leading to airway remodelling. Central to this doctoral thesis was the use of end-stage CF lungs in order to gain further insight into small airway disease and the inflammatory pattern eventually culminating in respiratory failure. Firstly, using high resolution computed tomography (HRCT) and micro-CT, we demonstrated that small airway disease in CF is a mixture of two processes, namely dilation and disappearance of these airways. This was illustrated by an increased number and diameter of visible airways of all generations in CF lungs compared with controls on the one hand, and a contrasting reduction of the number of terminal bronchioles, and severe small airway obstruction often followed by disappearance on the other hand. Based on our histological observations, this obliterative fibrosing occlusion may represent a repair mechanism triggered by airway destruction. Secondly, we identified the inflammatory pattern in the end-stage CF lung as featuring many players having a specific site of action. Next to several mediators of the innate immune system, also the cells of adaptive immune system, historically somewhat under-appreciated in CF due to their paucity in airway fluids, were quantified. We demonstrated large amounts of B cell follicles and also single T cells were abundantly present in the CF lung tissue. We found that there was a distinct shift in the ratio of CD4+ to CD8+ T cells from 2:1 in control subject to 1:6 respectively in CF patients. Combined with the significant increase of macrophages in CF compared with controls, this is suggestive of an extensive Th1-response possibly contributing to airway destruction and warranting further investigation. Finally, we touched upon a more controversial topic by investigating telomere dysfunction in the end-stage CF lung and peripheral blood leukocytes of CF patients. Studying ageing in CF patients is particularly interesting because of the ever-increasing life expectancy in this population. We demonstrated an association of several measures of disease severity such as lower forced expiratory volume in 1 second, CF asthma with need of inhaled corticosteroids and ΔF508 homozygosity, with shorter leukocyte telomere length (LTL). Also the non-linear age-dependant decrease in LTL attrition rate was influenced by genotype. This indicates that patients suffering from more severe disease exhibit increased cellular senescence, which may cause them to age faster and be more prone to age-related diseases. Given the specificities of telomere biology throughout life and our finding of a positive correlation between LTL measured at two time-points within the same individuals, these effects are probably already established during childhood, stressing the need for early diagnosis and the administration of CFTR-correcting therapy from an early age onwards. We could not demonstrate a link between telomere length and disease severity in CF lung tissue. This discrepancy between the lungs and the hematopoietic system may be attributed to the rate of cellular turnover within these tissues. In high-turnover tissues including the blood, telomere dysfunction will rapidly lead to cellular senescence, whereas in low-turnover tissues such as the lungs, telomere shortening is only one of the multiple hits eventually culminating in tissue debilitation.

During the course of this PhD, we came across an overt gender discrepancy on two different occasions. We first saw increased inflammation in the female end-stage CF lung, and then we found significantly longer LTL in female CF patients, possibly protecting against telomere-influencing factors. Taking into account our newly gained insights, we propose a model in which X chromosome-linked variability leads to both longer LTL and increased pulmonary inflammation in female CF patients. The latter will eventually lead to increased mortality and the so-called ‘CF gender gap’. Therefore, there is still a need for clinical trials with anti-inflammatory therapies including monoclonal antibodies, in which it may be wise to assess outcomes in females separately.