Cystic fibrosis is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which provides the instructions for making the CFTR protein. This protein is an ion channel that transports chloride ions and water across cell membranes. The mutation causes the CFTR protein to either not function properly or to not be made at all. This affects glands that produce mucus, sweat, saliva, tears, and digestive enzymes, leading to the production of thick and sticky mucus.
Normal mucus acts as a barrier to protect the airways by trapping inhaled particles and pathogens, preventing infections. Mucus is a complex, viscous secretion containing proteins, lipids, ions, and water. Its major component is a glycoprotein called mucin.
The thick mucus produced in CF can clog the airways and trap bacteria, resulting in persistent infections and inflammation. In addition to mucin, the mucus of CF patients contains abundant amounts of DNA and filamentous actin (F-actin) protein that is derived from dead inflammatory and epithelial cells trapped in the mucus.
Mucolytics are medications that decrease the viscosity of mucus by degrading the mucin polymers, DNA, or F-actin in airway secretions. This allows for better clearance of the sputum with a cough. There are three types of mucolytics: classic, peptide and non-destructive.
Classic mucolytics hydrolyze, or break down, mucin. The most commonly used classic mucolytics to overcome mucus obstruction in respiratory diseases are N-acetyl cysteine (NAC), erdosteine, and fudosteine.
Erdosteine is a mucolytic with antioxidant and anti-inflammatory properties. It interferes with the binding of bacteria to the epithelial cells lining the respiratory tract, reducing infections and inflammation.
Fudosteine inhibits the oversecretion of mucin by decreasing its biosynthesis. It also reduces airway hyper-responsiveness and airway inflammation.
NAC is the only classic mucolytic that has been used for the treatment of CF since the 1960s, taken either by mouth or via a nebulizer.
Pulmozyme is a recombinant human DNase, a protein that degrades DNA. DNA degradation provides access to the enzymes, which degrade proteins within the mucus. The breakdown of both DNA and proteins decreases the viscosity of mucus in CF patients. Pulmozyme also degrades bacterial DNA, sensitizing the bacteria to antibiotics.
Gelsolin is an actin-severing protein that breaks actin filaments by weakening the bonds between actin proteins in the F-actin network. In vitro studies have shown that gelsolin enhances the ability of dornase alfa to reduce the viscosity of the CF sputum by breaking down the F-actin network.
Tbeta4 is a peptide that increases the effectiveness of dornase alfa in reducing the viscosity of CF sputum by depolymerizing F-actin.
Gelsolin and tbeta4 have not been evaluated in clinical trials for the treatment of CF, and Pulmozyme is the only peptide mucolytic agent approved for the treatment of CF in the U.S.
Mucin in mucus is stabilized by polyionic interactions. Non-destructive mucolytics such as dextran and heparin are compounds with a low molecular weight that disrupt this polyionic mucin protein network. As a result, the sputum becomes less viscous. However, non-destructive mucolytics have not been evaluated for the treatment of airway disease in CF patients.
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