CF & SPLUNC1
Cystic fibrosis (CF) is an autosomal recessive genetic disorder affecting approximately 75,000 individuals worldwide, which is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The disease affects multiple organ systems including the lungs and respiratory tract, pancreas, intestine, liver and kidneys. However, the highest medical need is in the lungs, where complications from CF-related lung disease currently account for 80% of all CF deaths.
CF lung disease is hallmarked by dehydration of the fluid volume on the airway surface, resulting in reduced clearance of mucus, the lung's principle mechanism for cleansing itself. The mucus becomes thick and sticky, progressively accumulating into obstructions that are chronically colonized by viruses and bacteria, leading to frequent, acute lung infections, inflammation and loss of lung function. The long-term result of the constant insult from the infections and the body's own immune response is progressive, permanent tissue damage and scarring (fibrosis) in the lung that commonly requires lung transplantation and often leads to early death. No cure for cystic fibrosis is known, although several therapies have been approved to address the underlying cause of the disease in some patients. Despite these therapies, the median age of survival for CF patients is only 30-40 years of age.
SPLUNC1 is an extracellular protein secreted by epithelial cells into the airway fluid layer and which plays a role in down-regulating ENaC activity by promoting the internalization of the sodium channels via endocytosis. The regulatory effect is accomplished through the binding of an 18 amino acid peptide on the N-terminus of SPLUNC1, called S18, to the ENaC subunits, disrupting the sodium channel and initiating the intracellular collection of the subunits.
Unfortunately, SPLUNC1’s regulation of sodium channels in patients with CF is dysfunctional due to a structural change in the protein resulting from the acidic environment in the CF lung that inhibits the S18 peptide from binding to the sodium channels and causing internalization. Hyperabsorption of sodium results, beginning the vicious cycle of dehydration and stalling the natural mucociliary clearance that normally mobilizes mucus to remove embedded bacteria and foreign particles from the lung.
In the normal lung, the major ion channels, CFTR and the epithelial sodium channel (ENaC), work in opposing directions to tightly regulate the absorption and secretion of salt ions across the lung epithelium. This balanced regulation maintains the lung at a physiologically appropriate pH range and holds the airway surface liquid volumes at sufficient levels to support extension and beating of the cilia, promoting proper mucociliary clearance.
In the CF lung, mutated CFTR causes a reduction in lung pH and an imbalance in the regulation of salt ions that favors absorption of sodium via ENaC, with water following by diffusion. The acidic environment of the CF lung further reduces the regulation of ENaC, allowing these channels to become hyperabsorbing, amplifying the dehydration of the airway surface. The lack of sufficient fluid volumes causes the cilia to collapse and the mucus to become thick and immobile, leading to mucus accumulation and the beginning of the downward cycle toward lung disease.