Cystic Fibrosis-Possible Treatment Target Identified

Highlights

• Cystic fibrosis (CF) is a genetic disease that affects the mucus and sweat glands of various organs in the body, including lungs.
• In people with CF, proteins called mucin fail to unfold normally in the airways thus making the mucus more thick and sticky.
• This sticky mucus clogs the lungs making it easy for pathogens to keep growing and causing chronic infection, ultimately leading to lung damage and shortened life span.

Cystic fibrosis is a rare genetic disease that affects about 70,000 people worldwide. It affects the mucus and sweat glands of the lungs, pancreas, liver, intestines and sinuses. It causes the mucus to be thick and sticky. CF occurs when a person has two defective copies of the CFTR gene, which triggers the creation of the CFTR protein. When that protein is mutated, it results in cystic fibrosis.

In healthy people, CFTR allows chloride and other ions to flow out of cells.

"Those chloride ions essentially hold water outside the cells," Kesimer said. "We need that water there. When that flow of chloride is reduced, the airway surfaces become dehydrated."

In people with CF, this lack of water is accompanied by a thickening and increased stickiness of the mucus layer.

People suffering from cystic fibrosis (CF) get frequent lung infections because their airway mucus is too thick and sticky. The sticky mucus, which is composed of many kinds of proteins called mucins, does not move like it should.

It clogs the lungs and makes it easy for bacteria, viruses, and other pathogens to keep growing and causing chronic infection. This can eventually lead to lung damage and shortened lifespan.

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Mechanism of Sticky Mucus

In the new study, the research team found that in cystic fibrosis patients, proteins called mucin, that gives mucus its gel-like consistency, fail to unfold normally in the airways thus making the mucus more thick and sticky.

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Under ordinary circumstances, the mucin proteins are secreted from cells in a tightly packed form and they unfold rapidly into elongated, linear molecules, giving mucus the consistency it needs to clear airway surfaces and protect the lungs.

"In healthy people - after airway surface cells secrete mucins - the proteins unfold from a compact form to a more open, linear form," said senior author Mehmet Kesimer, PhD, associate professor of pathology and laboratory medicine and member of the UNC Marsico Lung Institute. "And we found that this unfolding process is defective in CF airway epithelia."

Mucin proteins, particularly the dominant one called MUC5B, in healthy epithelial cells or human saliva, unfold into more open, linear forms within a few minutes to a few hours of being secreted.

But in CF, MUCB5 usually remained in a compact form. Electron microscopy revealed an abnormally dense structure for the MUCB5 secreted by CF cells.

Blocking Flow of Chloride Ions

In the next step, researchers blocked the flow of chloride ions from the cells. This reduces the watery layer lining the airway surface which resulted in mucin proteins persisting in their compact form.

The dehydration of airway surface then triggered increased concentration of MUCB5.

This work suggests that depletion of the normal water layer on airway surfaces is the principal reason why MUCB5 fails to unfold normally. There is more evidence that the key to the mucins is the watery layer upon which the mucus glides.

Kesimer said, "We did experiments with saliva, primary human cells, and even the tracheas of pigs, and they all indicated that dehydration is the critical factor."

Conclusion

Clinical trials already have found evidence that inhaled hypertonic saline, sterile salty water, which helps restore a normal ionic balance to the airway and rehydrate it, helps in thinning the mucus and slows the decline of lung function.

Researchers are also targeting chemical bonds within mucin proteins. This approach may break up the abnormally large and dense forms of MUCB5 into smaller fragments to benefit CF patients.

The findings suggest that therapies to rehydrate the airway lining might restore normal MUCB5 function and thin out the mucus sufficiently to provide a benefit for CF patients.

The mechanism by which mucus becomes abnormal in CF airways was explained by researchers from the UNC School of Medicine and their findings are published in JCI Insight.

Reference

1. Cystic Fibrosis - (https://medlineplus.gov/cysticfibrosis.html)

Source-Medindia