Cystic Fibrosis (CF) is a rare and deadly genetic disease that affects about 70,000 people worldwide. It is caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, which alters ionic fluxes. Under normal conditions, the CFTR gene codes for a cAMP-governed ion channel for chlorine secretions and but also down-regulates the Epithelial Sodium Channel (ENaC). CFTR and ENaC control water movement through the epithelium of mucous membranes.
In CF, defective CFTR results in abnormal mucus accumulation, which initiates inflammation and bacterial infection. Furthermore, this vicious cycle of inflammation/infection is also influenced by the fact that CFTR plays an important role in the movement of bicarbonate ions (HCO3-) as well and when defective, lowers epithelial surface pH, hindering bacterial death. These processes lead to a slow loss of function of the lungs, making it more difficult for CF patients to breathe and exercise in early stages of the diseases and by the later stages, the lung structure itself changes causing hypertension, hemoptysis, and hypoxia.
Mucus obstruction plays a key role in the progression of CF lung disease. The biophysical properties of mucus are derived from large O-linked glycoproteins called mucins that form complex polymers. Mucins are heavily glycosylated to provide water retention and swelling properties to mucus gels. In addition to the glycosylated areas, there are numerous N- and C-terminal cysteine-rich domains scattered throughout the mucin protein backbone which are involved in the polymeric organization of the mucin network by forming disulfide bridges. The biochemical structure of the mucins provides the basis for the functions and biophysical properties of the mucus.
Mucus produced in the lungs has two functions: to trap/clear pathogens and to enhance transport/flow. In the lungs, mucus comprises of two separate mucins, MUC5B, the dominant mucin, and MUC5AC which is upregulated during pathogen infection. Both mucins are likely to possess different viscoelastic properties and play a distinctive role in the disease. For a long time, MUC5AC and MUC5B were thought to function equally in the lungs but recent studies have indicated that MUC5AC may have different biochemical and biophysical properties than MUC5B and as a result, MUC5AC is upregulated in muco-obstructive diseases. Evidence for this exists in the fact that in diseases such as CF, MUC5AC has a higher concentration in the lungs, potentially causing some of the observed symptoms (e.g., mucus plug formation). Other studies have also indicated that MUC5AC may be responsible for a slower mucociliary clearance (MCC), but more work is needed to further corroborate these observations.
It is important to understand the biochemical and biophysical properties of these two mucins as a way to further develop treatments for CF. There are hundreds of mutations which can cause a defective CFTR protein, hence it is complicated to target the protein directly, although impressive progress has been made in the field of CF research. Regardless of genotype, the one common problem that all CF patients present with is mucus accumulation at an early stage of the disease, which initiates the pathogenesis cascade of chronic inflammation and bacterial infection. Hence, the development of mucoactive therapies, dependent on a good understanding of mucin properties and roles, maybe a valuable investment of time and capital as treatments are independent of patient genotype and inflammatory status.
Co-founder and Editor of StemTalksNC