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Cystic Fibrosis Discovery May Lead to New Treatment Strategy

Inflammation turns liquid mucus into elastic sludge

A team led by University of California, San Francisco professor of medicine John Fahy, MD, has discovered why mucus in the lungs of people with cystic fibrosis (CF) is thick, sticky, and difficult to cough up, leaving these patients more vulnerable to lung infection.

Fahy and his colleagues found that in CF –– contrary to previous belief –– inflammation causes new molecular bonds to form within mucus, transforming it from a liquid to an elastic sludge. The scientists also made headway in the lab in exploring a potential new therapeutic approach to dissolve those bonds and return the mucus to a liquid that is easier for the lungs to clear.

Fahy said that the research has implications for other lung conditions characterized by thickened mucus, such as chronic obstructive pulmonary disorder (COPD) and asthma.

The findings were published February 25 in Science Translational Medicine

Polymers in mucus are the key to the discovery. Until now, scientists had thought that CF mucus is thicker than healthy mucus because it has a greater concentration of DNA polymers. To test that idea, Fahy and his team exposed mucus samples taken from CF patients to two current CF medications: dornase alfa (Pulmozyme, Genentech), a drug that breaks up DNA polymers, and N-acetylcysteine (NAC), which targets disulfide bonds between mucin polymers. Mucin proteins are the major constituents of mucus.

“We thought Pulmozyme would be more effective than NAC in liquefying the mucus, because CF sputum contains lots of DNA,” said Fahy. “But to our surprise, NAC worked much better.”

Using microscopy, the scientists learned why: CF mucus consists of a dense core of mucin with a layer of DNA wrapped around it, like a thin blanket draped over a solid pillow. Thus, while Pulmozyme makes mucus less stiff by eliminating DNA, NAC liquefies it by breaking up the mucin.

Fahy and his colleagues then investigated why mucin in CF is so compacted. They found that mucin polymers become linked together crosswise by newly forged disulfide bonds. Fahy likened the polymers to logs floating down a river. “The logs can float down the river as long as they are floating independently,” he said. “But if you bolt them together side to side, they will clog the river.”

The researchers found that inflammation causes the extra disulfide bonds to form when mucin polymers are exposed to highly reactive oxygen molecules released by inflammatory cells in a process called oxidative stress.

This observation was confirmed by a device invented by lead investigator Dr. Leo Shao-peng Yuan, of the UCSF Cardiovascular Research Institute. In separate chambers, mucus from healthy volunteers was exposed to pure oxygen and pure nitrogen. The mucus exposed to oxygen became thick and elastic within seconds. The mucus exposed to nitrogen remained liquid.

Fahy noted that patients who are treated with pure oxygen in hospital intensive-care units have been known to develop sticky mucus. “This could be a function of the oxygen that’s used to treat them,” he said.

Finally, the research team turned its attention to the possibility of creating new treatments for CF that would directly target disulfide bonds in mucin polymers.

NAC, which targets mucin polymer bonds, is already an approved medication used to break up mucus. “However,” said Fahy, “there are problems with it. It’s a relatively weak drug, and it smells like rotten eggs.”

Team member Stefan Oscarson, PhD, a medicinal chemist, designed TDG, an experimental compound that targets disulfide bonds. TDG was found to liquefy mucus samples from CF patients much more efficiently than NAC. Fahy cautioned, however, that TDG cannot yet be given to human subjects.

Fahy predicted that the new finding will explain the reason for thick mucus in other lung diseases known to be associated with oxidative stress, including COPD and asthma. “We’re very confident that we’ve uncovered a ubiquitous mechanism here,” he said.

Source: UCSF; February 25, 2015.

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