Cystic fibrosis discovery offers path for creating, testing treatments

UNC School of Medicine researchers have provided the first quantitative evidence that mucins – the protein framework of mucus – are significantly increased in cystic fibrosis patients and play a major role in failing lung function.

The research, published today 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,” said Mehmet Kesimer, PhD, associate professor of pathology and laboratory medicine and co-senior author of the JCI paper.

Ashley Henderson, MD, assistant professor of medicine and co-first author of the JCI paper, added, “We think this study shows why nebulized hypertonic saline [sterile salty water] improves the hydration of the CF airway, improves the patient’s mucus clearance and, in so doing, increases lung function.”

The UNC study also casts further doubt on a controversial 2004 study that disputed the theory that mucins play a major role in CF.

This work, a collaboration of 13 UNC scientists, is part of an extensive UNC lung research program based in the new Marsico Lung Institute, which is led by Richard Boucher, MD, co-senior author of the JCI paper.

“This paper points to a therapeutic strategy to rectify this problem of mucus clearance and provides signposts, or biomarkers, to guide development of novel therapies,” said Boucher, the James C. Moeser Eminent Distinguished Professor of Medicine. Also, by measuring mucin concentration in patient mucus, doctors could learn whether therapies are working and to what degree.

Scientists and doctors have known for a long time that failing to clear mucus is the major reason why CF patients face chronic lung infection and inflammation. But the mechanisms of this failure have not been well understood.

Normally, 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.

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By Mark Derewicz, School of Medicine.

June 4, 2014.