CF affects the epithelial lining of many organs but most significantly the airway epithelium of the lung. Mutations in the CFTR gene lead to the production of a misfolded CFTR protein which cannot be transported properly to the cell surface or is non-functional when it does get there.
Ironically, in non-CF individuals the CFTR gene is expressed at very low levels in most cells of the lung. However, due the the complexity of CFTR's interactions with other proteins (which are still not fully understood) and the importance of the airway in clearing possible infectious agents, loss of function results in CF lung disease.
Under normal conditions the CFTR protein functions as a chloride channel pumping Cl- ions out of the cell. CFTR also functions as a regulator of other channels. When active, the NBF1 region of CFTR has an inhibitory effect on the epithelial sodium channel (ENaC).
When non-functioning CFTR is produced or when no CFTR is produced the chloride balance within cells is altered dramatically. ENaC is released from its inhibition and an increase in sodium conductance is observed. This leads to abnormal 'salty' cellular secretions which promote bacterial colonisation of the lungs and ultimately cause lung damage in CF patients.
Loss of CFTR function leads to impaired lung defences and inflammation.
The loss of CFTR function leads to changes in the airway surface liquid lining the lungs. This impairs the lung clearance mechanisms and means that individuals with CF are prone to chronic inflammation and bacterial infection.
The bronchoalveolar lavage fluid (BALF) from patients with CF contains elevated levels of the pro-inflammatory cytokines IL-1β, TNF-α, IL-6 and IL-8 compared to non-CF controls (Bonfield et al., 1995b). These cytokines function as signalling molecules to help fight infection and they recruit white blood cells (neutrophils) into the airways.
Although neutrophils are intended to control infection, in CF the massive numbers that infiltrate the airways cause tissue damage due to the secretion of excessive amounts of elastase and other proteinases (Konstan & Berger, 1997). Elastase causes lung damage by digesting structural proteins, which leads to bronchiectasis. DNA released from dead neutrophils is one of the prime factors that contribute to the increased viscosity of CF sputum (Chernick & Barbero, 1959; Fuchs et al., 1994). This led to the development of Pulmozyme (human DNaseI) as a therapy for CF. Furthermore, the airway epithelia of patients with CF secrete very low levels of the anti-inflammatory cytokine IL-10.
Since the discovery of the CFTR gene, researchers have struggled to find a cohesive explanation for how the lack of a modestly expressed Cl- channel can lead to the development of the complex disease that is CF.
Today, a picture is emerging of a disease with multiple determinants of pathology. Airway dehydration and compaction of mucus, abnormal and inflated inflammatory responses and perhaps the lack of some developmental function combine and synergise to produce a complex disease progression.
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