Abnormally thick and sticky mucus that clogs airways and makes the lungs more vulnerable to persistent, difficult-to-treat bacterial infections is a major problem for people with cystic fibrosis (CF), especially in its more advanced stages.
Understanding why CF mucus is so sticky may suggest ways to more effectively treat the problem.
A recent study by researchers at the University of Iowa’s Pappajohn Biomedical Institute (PBI) suggests that CF patients’ excessively sticky mucus is present from birth, rather than a problem that develops over time. Moreover, the study suggests that this mucus is more viscous in CF patients because a thin layer of liquid that coats our airways is more acidic in those who have the condition.
The gene mutations that cause CF disrupt the function of a protein called the cystic fibrosis transmembrane conductance regulator (CFTR) channel, which secretes bicarbonate ions into the airway surface liquid. Higher levels of bicarbonate ions reduce the airway surface liquid’s acidity.
Prior work from the lab of Michael Welsh, UI professor of internal medicine and director of the PBI, showed that loss of the CFTR channel leads to increased acidity in airway surface liquid in both human patient and pigs with CF
“Previous studies showed that acidity and bicarbonate ions both can affect the physical properties of mucus,” say Xiao Xiao (Sammi) Tang, lead author of the new study and a postdoctoral scholar in Welsh’s lab. “Therefore, it remained unclear whether it is the increased acidity and/or the concentration of bicarbonate ions that leads to an increased viscosity in CF airway surface liquid.”
Using the pig model of CF, Tang and her colleagues were able to differentiate the effects of acidity and the effects of bicarbonate levels, showing that increased airway-surface-liquid viscosity was a result of increased acidity, not lower concentrations of bicarbonate.
The new study, published in the March issue of the Journal of Clinical Investigation, suggests that increased airway-surface-liquid acidity changes the way mucin molecules interact. Mucin is a major protein component of mucus.
Tang also investigated other biophysical factors that could affect mucus viscosity.
“The results of our study suggest that decreasing acidity, reducing calcium concentration, and/or altering electrostatic interactions (of mucus proteins) in airway surface liquid could decrease mucus viscosity and, therefore, might benefit patients in the early stages of CF,” she says.
For example, the study suggests that a current therapy using hypertonic saline, which appears to improve airway clearance in people with CF, may produce its beneficial effect, at least in part, by altering electrostatic interactions in mucus.
Tang notes that the findings may also be relevant for other respiratory diseases in which the airway surface liquid is more acidic than normal, including asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome.
In addition to Tang and Welsh, the UI research team included Lynda Ostedgaard, Mark Hoegger, Thomas Moninger, Philip Karp, James McMenimen, Biswa Choudhury, Ajit Varki, and David Stoltz.
The research was funded in part by grants from the National Heart, Lung, and Blood Institute, the Cystic Fibrosis Foundation, and the Roy J. Carver Charitable Trust.