A collaborative research team from the University of California in San Francisco (UCSF), the Cleveland Clinic in Ohio, and University College Dublin (UCD) in Ireland, recently revealed the reason why individuals suffering from cystic fibrosis (CF) accumulate sticky mucus in their lungs, making them more prone to lung infections. The study was published in the journal Science Translational Medicine and is entitled “Oxidation increases mucin polymer cross-links to stiffen airway mucus gels.”
CF is a life-threatening genetic disease in which a defective gene causes the body to form unusually thick, sticky mucus that is difficult to cough up and can result in serious respiratory and gastrointestinal manifestations. In the United States alone, it is estimated that around 30,000 children and adults suffer from CF with 1,000 new cases diagnosed every year. Currently there is no cure for CF.
CF mucus is thicker due to a higher concentration of DNA polymers, which are natural molecules present in the mucus capable of forming long chains. To confirm this theory, the team exposed mucus from CF patients to two available medications for CF: Pulmozyme, a drug that destroys DNA polymers, and N-acetylcysteine (NAC), a drug that targets disulfide bonds between mucin (the main protein present in the mucus) polymers.
“We thought Pulmozyme would be more effective than NAC in liquefying the mucus, because CF sputum contains lots of DNA,” said the study’s senior author Dr. John Fahy in a news release. “But to our surprise, NAC worked much better.” With the help of confocal microcopy, researchers found that CF mucus has a molecular architecture composed of a dense core of mucin proteins surrounded by a layer of DNA. Pulmozyme eliminates this DNA layer while NAC liquefies the mucus by breaking up the mucin core.
Researchers discovered that inflammation in CF leads to the generation of extra molecular bonds within the mucus (called disulfide bonds) due to the exposure of mucin polymers to highly reactive oxygen molecules produced by inflammatory cells in a process called oxidative stress; these extra bonds result in the conversion of mucus from a liquid form to an elastic sludge. It was found that the higher the level of reactive oxygen species in CF mucus, the higher the concentration of disulfide bonds.
“This qualitative change, driven by oxidation, happens with other natural polymers,” explained Dr. Fahy. “Think of latex, which starts out as liquid tree sap. When it’s vulcanized — a process of chemical cross-linking — it turns into the solid rubber we use in tires.”
The mucus of CF patients treated with pure oxygen in intensive care units is known to become thick, sticky and elastic, an observation that “could be a function of the oxygen that’s used to treat them,” proposed Dr. Fahy.
When evaluating an experimental compound developed at UCD, called TDG, which also targets disulfide bonds in mucyn polymers, the team found it to liquefy CF mucus samples more efficiently than NAC. Dr. Fahy is, however, cautious and claims that “there are at least five years of testing ahead before we can say we have a new medication.”
The team believes that their findings can be applicable to other lung diseases also characterized by the production of thick mucus, related to oxidative stress like asthma and chronic obstructive pulmonary disorder (COPD). “We’re very confident that we’ve uncovered a ubiquitous mechanism here,” concluded Dr. Fahy. Researchers suggest a possible new therapeutic approach based on the dissolution of disulfide bonds within the mucus to transform it back to a liquid form, which is easier for the lungs to clear.