Date of Award
MD (Medical Doctor)
Dr Catherine Greene
Professor N.G. McElvaney
Cystic Fibrosis, Immunity, Innate, Child.
Cystic Fibrosis, the commonest lethal hereditary disorder in Caucasians, is characterised by recurrent respiratory infection, progressive inflammation and lung damage, and ultimately respiratory failure. In CF, recurrent infection occurs only in the respiratory tract and not elsewhere, implicating a localised abnormality of innate defence in the lungs. Several bacteria can cause CF lung infection, the most important and clinically significant of which is P, aeruginosa. Chronic infection with this organism is associated with an increase in morbidity and mortality. We sought to determine whether different degrees of P. aeruginosa lung infection were linked to abnormalities of the pulmonary innate defence and lung inflammation. We also sought to examine the effect of the external factors of vitamin D status and pulmonary aspiration on lung inflammation.
We demonstrated a significant further derangement in protease anti-protease balance in those with chronic infection compared to all others with CF, with higher free neutrophil elastase and cathepsin levels, and lower levels of SLPI and elafin. Neutrophil elastase levels correlated very clearly with lung function. The chronically infected group also showed a shift towards a Th2 cytokine response in BAL with elevated levels of IL-4, reduced levels of IFN- y and an increased IL-4: IFN-y ratio compared to other CF groups. We demonstrated a significant reduction in levels of both IL-6 and MCP-1 in the chronically infected group, which may be related to degradation by airway proteases. We showed that Vitamin D and it's analogues can act to reduce pro-inflammatory cytokine release from stimulated respiratory epithelial cells in CF through an inhibition of IkBɑ.Vitamin D levels were lower in children with chronic P. aeruginosa infection compared to other groups but were not linked to differences in lung function or inflammation. We demonstrated evidence of pulmonary aspiration in a subset of children with CF by finding elevated pepsin levels in BAL,, and showed that the levels of pepsin were closely correlated to IL-8 levels.
This thesis sheds new light on the pulmonary innate defence system in children with CF at various stages of P. aeruginosa infection and confirms the beneficial and deleterious effects respectively of vitamin D and pulmonary aspiration on inflammation in the CF lung.
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McNally P. Abnormalities in the pulmonary innate defence in children with cystic fibrosis : relationship to pseudomonas aeruginosa infection [MD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2011.