Public Release: 

The mechanism of mucus: Discovery could lead to better cystic fibrosis treatments

University of North Carolina Health Care


IMAGE: This is an electron microscopy of large, compact mucin protein that keeps mucus too thick and sticky, causing problems for CF patients. view more

Credit: M. Kesimer/J. Griffith, UNC School of Medicine


"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."



"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."

For reasons that haven't been entirely clear, the lack of water in people with CF is accompanied by a thickening and increased stickiness of the mucus layer. The sticky mucus - which is composed of many kinds of proteins - doesn't move like it should. Pathogens, such as bacteria, become trapped in the lung. This faulty process leads to progressive lung damage and a shortened lifespan.

In prior work, Kesimer and colleagues showed that an abnormally high concentration of mucins contributes to mucus thickness and stickiness. Kesimer and his team also had demonstrated that mucin proteins, under ordinary circumstances, are secreted from cells in a tightly packed form - because they are so large - and then they unfold rapidly into elongated, linear molecules, giving mucus the consistency it needs to clear airway surfaces and protect the lungs.

In the new study, Kesimer and his team found evidence that this mucin unfolding process fails to occur normally in CF airways. In healthy epithelial human cells or in human saliva, mucin proteins - particularly the dominant one called MUC5B - typically morph into more open, linear forms within a few minutes to a few hours of being secreted. By contrast, MUCB5 from CF cells usually remained in a compact form. Electron microscopy revealed an abnormally dense structure for the MUCB5 secreted by CF cells.



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."

This work suggests therapies to rehydrate the airway lining might restore normal MUCB5 function and thin out the mucus sufficiently to provide a benefit for patients. 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 - thins mucus and slows the decline of lung function.





