Scientists and doctors have known for a long time that failing to clear mucus is the major reason why people with cystic fibrosis face chronic lung infection and inflammation. But it wasn’t clear why.
A recent study suggests that higher concentration of mucins, the proteins that give mucus its gel-like quality, may offer clues.
The research, published in the Journal of Clinical Investigation, shows that a three-fold increase of mucins dramatically increases the water-draining power of the mucus layer. This hinders mucus clearance in the CF lung, resulting in infection, inflammation, and ultimately lung failure.
“Our finding suggests that diluting the concentration of mucins in CF mucus is a key to better treatments,” says Mehmet Kesimer, associate professor of pathology and laboratory medicine at the UNC School of Medicine and one of the paper’s senior authors.
Ashley Henderson, assistant professor of medicine and co-first author of the paper, says the results suggest why nebulized saline treatments improve airway hydration and mucus clearance.
The new findings cast more doubt on a controversial 2004 study that disputed the theory that mucins play a major role in CF.
How we normally clear mucus
When we breathe, the mucosal layer of our lungs trap the contaminants—dust, pollutants, bacteria—naturally found in air.
Then, epithelial cells with hair-like cilia brush the mucus up and out of our lungs. In people with cystic fibrosis, though, this process doesn’t work as well because they lack a properly functioning CFTR gene. They continually battle infections and must work hard to clear mucus from their lungs.
This is where mucins come into play. Mucins give mucus its gel-like thickness and elasticity.
“Without mucins, mucus would have the viscosity of blood,” Kesimer says. “The vast majority of mucus is water, but 30 to 35 percent of the remaining solid material is made up of mucins. They form a network of bonds that serves as a framework.”
This is why Kesimer and colleagues suspected that something must happen to mucins in the CF lung. They and others knew that CF mucus is typically drier than normal mucus.
Why the 2004 study was wrong
Back in 2004, however, other researchers used a standard immunologic analysis to show that mucins were decreased in CF secretions. They suspected DNA was the main culprit that caused problems in CF mucus.
Kesimer and others were skeptical. To investigate, they used a technique called size exclusion chromatography: in a column, they added custom-made beads that had small pores. Smaller proteins could enter the pores while mucins could not.
Through this separation, the team isolated the mucins and simultaneously measured their concentration using a refractometer.
By using sputum samples from CF patients, the researchers found that CF mucus contained three times as many mucins than did normal samples. They also conducted experiments to show that mucin overabundance led to a six-fold increase of the pressure between the mucus layer and the ciliated layer.
This finding affirms that in a CF patient, the increased osmotic pressure of the concentrated mucus layer crushes the ciliated cells so that mucus is not cleared. The lung becomes a breeding ground for bacteria. This leads to more mucins, more mucus, inflammation, and subsequently lung failure.
The National Institutes of Health and the Cystic Fibrosis Foundation funded this research.