Increased acidity may affect mucus viscosity by altering electrostatic interactions between mucin molecules

Abnormally thick and sticky mucus that clogs airways and makes the lungs more vulnerable to persistent, difficult-to-treat bacterial infections, is a major clinical 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, and potentially improve the respiratory health of people with CF.

A recent study by researchers at the Pappajohn Biomedical Institute (PBI) at the University of Iowa suggests that excessively sticky mucus is a primary defect of CF that is present from birth, rather than a problem that develops over time as the disease progresses. Moreover, the study suggests that the mucus is more viscous because the thin layer of liquid coating the airways is more acidic in CF airways.

The gene mutations that cause CF disrupt the function of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, which secretes bicarbonate ions into the airway surface liquid (ASL). Higher levels of bicarbonate ions reduce the acidity of the airway surface liquid. Previous work from the lab of Michael Welsh, MD, UI professor of internal medicine, molecular physiology, and biophysics; a Howard Hughes Medical Institute Investigator; and director of the PBI, shows that loss of the CFTR channel markedly reduces bicarbonate secretion and leads to increased ASL acidity.

“Previous studies showed that acidity and bicarbonate ions both can affect the physical properties of mucus,” say Xiao Xiao (Sammi) Tang, PhD, 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 a pig model of CF, Tang and her colleagues were able to separate the effects of acidity and bicarbonate concentration and show that airway surface liquid viscosity is increased in CF because of the increased ASL acidity, not because of reduced bicarbonate concentration.

The new study, published in the March issue of the Journal of Clinical Investigation, suggests that increased ASL acidity affects mucus viscosity by altering the strength of electrostatic interactions between mucin molecules. Mucin is a major protein component of mucus.

Tang also investigated other biophysical factors related to mucus and the ASL 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 (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 where 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.

Story Source: Jennifer Brown, UI Health Care Marketing and Communications, 200 Hawkins Drive, Room W319 GH, Iowa City, Iowa 52242-1009

Media Contact: Jennifer Brown, UI Health Care Marketing and Communications, jennifer-l-brown@uiowa.edu