Correct!
2. Cl ion channel mutation
Cystic fibrosis is one of the most common genetic diseases in Caucasian population. It is caused by a single mutation in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene which codes a protein that functions as a chloride ion channel, however, also regulates other ion channels’ activity and signal transduction (3). There are six main classes of CFTR mutations. Class I stands for mutations rendering no CFTR protein production due to either stop codon or splicing mutation. Class II mutations result in a protein trafficking defect and early degradation from protein mis-folding. Phe508del, the most common mutation in Caucasian population, belongs to class II. Class III, IV, V and VI stand for mutations of ATP binding, channel gating, transcriptional deficiency or splicing abnormality and accelerated protein turn-over from the apical membrane, respectively (figure 2).
Figure 2. Classification of CFTR mutations.
The clinical manifestations of the same genotype can be very different between individuals depending on polymorphisms in other genes and environmental factors (4). The US Cystic Fibrosis Foundation suggests sweat testing as the most reliable and useful screening test for cystic fibrosis and it is recommended in all patients who have symptoms and signs of cystic fibrosis (5).
Mucosal obstruction and constant inflammation are the two major contributing factors for the decline of pulmonary function in cystic fibrosis, and they increase the mortality. Submucosal gland ducts in cystic fibrosis are filled with viscous mucus, and this provides a favorable environment for bacterial colonization such as Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepacia. As the disease progresses, these pathogens eventually form a biofilm and produce capsular polysaccharide which prevent antibiotics from penetrating into the bacteria, and facilitate resistance formation. Moreover, the mucus is filled with inflammatory cells that release inflammatory cytokines such as IL-6, IL-8, TNF-α and LTB4.These cytokines exacerbate the structural destruction of lung via constant inflammation.
Although the pathology and clinical course of cystic fibrosis are well understood, the underlying mechanisms connecting CFTR dysfunction to organ damage remain elusive. Two main hypothesis have been postulated: the “low-volume” and the “high-salt” hypotheses (Figure 3).
Figure 3. Models explaining viscous mucus plug formation and chronic infection in the airway of cystic fibrosis.
In the low-volume model, excess sodium and water accumulate in epithelial cells causing dehydration at the airway surface. Concurrent loss of chloride ion efflux from the epithelium to the airway surface fails to correct the water volume loss resulting in thick mucus plug formation (6). High-salt models postulate that excess sodium and chloride ions accumulate at the airway surface due to lack of CFTR function. The high concentration of these ions inhibits endogenous anti-microbial peptides such as human β-defensin 1, allowing bacterial over-growth in the viscous mucus plug (7).
Collectively, CFTR dysfunction causes viscous mucus formation in the airway surface, and subsequently facilitates bacterial colonization. Neutrophils and inflammatory cytokines in this microenvironment exacerbate the destruction of the lung and consequently results in chronic bronchitis and bronchiectasis, which are seen in the imaging (Figure 1). This vicious cycle is further enhanced by the overgrowth of the bacteria causing acute exacerbations and decline of pulmonary function, which contribute to morbidity and mortality.
Which of the following is associated with pulmonary function improvement or prevention of acute exacerbations in cystic fibrosis patients? (Click on the correct answer to move to the next panel)