Underlying molecular defect

CF is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is a cAMP regulated chloride channel, which opens in response to phosphorylation by ATP. CFTR is found in sweat and pancreatic ducts, gut, seminiferous tubules, conducting airways and many other tissues. Most often mutations lead to either CFTR not reaching the apical membrane or alternatively reaching it, but having reduced function. This results in impaired chloride transport at the apical surface of the epithelial cells. In addition absorption of sodium from the airway surface is increased in CF. CFTR negatively regulates the activity of the sodium channel ENaC and mutations in CFTR alter this regulation leading to the increased sodium absorption characteristic of CF. CFTR also regulates many other proteins. For an excellent animated guide to CFTR function please click here.

Link between clinical pathology and molecular defect

It remains unclear exactly how the altered production of CFTR results in the pathology observed in CF. There are a number of theories. At present the extent to which each of these contributes, if at all, to the observed pathology has not been established.

The low volume hypothesis proposes that due to the impaired chloride secretion and the high sodium absorption, water is absorbed and the airway surface liquid becomes depleted. This renders the cilia unable to beat effectively and the mucociliary clearance of secretions and bacteria is impaired leading to the increased susceptibility to infection seen in CF subjects. 

The high salt hypothesis suggests that the impaired chloride transport results in abnormally high salt concentrations in the airway surface liquid, which reduces the effectiveness of natural antibiotics such as defensins, lysozyme and lactoferrin and consequentially resistance to bacterial infection. 

There is also evidence to suggest that mutations in CFTR result in an increased number of pathogen receptors on respiratory cells. This leads to the increased binding of bacterial pathogens, including P. aeruginosa that is observed in CF airways.

It is believed that CFTR may be involved in the ingestion of the bacterium P. aeruginosa into epithelial cells and its clearance from the lungs. The mechanism is poorly understood at present. However in the absence of CFTR it is thought that this process is unable to occur efficiently resulting in the increased numbers of bacteria in the lungs characteristic of CF. 

In all these theories, although the underlying processes vary, the basic CF defect predicts a compromise in the innate defences of the lung, allowing retention of bacteria and the associated inflammation. Controversially it has also been suggested that the CFTR mutation alone may be responsible for inflammatory changes in the early CF lung without concomitant bacterial infection. It is hypothesised that abnormal CFTR protein accumulates in the endoplasmic reticulum (ER) of CF cells. This is thought to have the downstream effect of activating transcription factors such as nuclear factor kappa B (NFkB). These factors are responsible for the up regulation of many pro-inflammatory cytokines including interleukin-8.

Links to further information on:

CFTR Mutations

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