The mucous membranes in the airways of people with cystic fibrosis produce mucus that is thick and viscous, more solid than is produced by healthy people, which leads to all sorts of problems in the patient.
As anyone with CF knows, the reason the mucus thickens is because the proteins that form the mucus fail to assume the correct shape. Improperly shaped proteins lead to thick mucus, which leads to trouble breathing.
But what causes the proteins to fail to be shaped correctly? We know that cystic fibrosis is a hereditary disease caused by a mutation of a specific gene, that of the cystic fibrosis transmembrane conductance regulator protein. But that is not the same as knowing how that mutation causes the issues.
The answer may be simpler than most people expect. A recent study has come to the conclusion that the physiological method by which cystic fibrosis causes proteins to be formed incorrectly is a lack of water.
Unfortunately, merely drinking more water may not help. The issue is at the cellular level in the cells of the airways. They are what is dehydrated, not your overall level of hydration.
Water in the Cells
The mucous cells of healthy people, specifically submucosal glands in the lungs and other airways, produce mucus proteins called mucins, also known as MUC5B. Once released, the mucins unfold and make themselves more open and linear, though this can take anywhere from a few minutes to a few hours.
“And we found that this unfolding process is defective in CF airway epithelia,” said Mehmet Kesimer, PhD, associate professor of pathology and laboratory medicine at the University of North Carolina at Chapel Hill.
Merely being in a compact state instead of unfolded would not be as large of a problem as it is. The MUC5B mucins are not just compact when they are released, they are also clumped together with other mucins. In healthy people, they separate from these clumps when unfolding.
Part of what triggers these mucins to unfold is a healthy amount of water in the surrounding tissue. When that water level is deficient then the mucins fail to unfold, and the mucus thickens. Also, the lack of water itself contributes to the thickness of the mucus.
Cystic fibrosis patients have a reduced amount of chloride ions, which are used by the body as tiny water pumps for your cells. Without the chloride ion water pumps, the water cannot flow into and out of your cells properly, so water is not maintained outside of the airway cells, and your airways are dehydrated.
Thick mucus does not transport pathogens out of your body before they can cause trouble, and the thick mucus can make it hard to breathe. Just a little dehydration thereby causes large problems.
The researchers were Lubna H. Abdullah, Jessica R. Evans, T. Tiffany Wang, Amina A. Ford, Alexander M. Makhov, Kristine Nguyen, Raymond D. Coakley, Jack D. Griffith, C. William Davis, Stephen T. Ballard, and Mehmet Kesimer. They published their results in the JCI Insight journal on March 23, 2017.
Some of the researchers were veterans of cystic fibrosis research and had been important in discovering that MUC5B’s failure to unfold is part of what causes the symptoms of cystic fibrosis. While performing that research they noticed that the airways of people with the disease seemed less hydrated than the airways of healthy people, and thus went down this line of questioning.
Cells from people without cystic fibrosis were used for the control group, and cells from people with the disease were used for the experimental group. Domestic pig cells were also used, both for control and as the experimental group.
The University of South Alabama Institutional Animal Care and Use Committee ensured that the researchers followed the United States Public Health Service Policy on Humane Care and Use of Laboratory Animals.
The researchers used secretions from primary human tracheobronchial cell cultures and stimulated them to produce the mucus proteins. They collected these proteins two minutes after stimulation, an hour after, and four hours later.
They then examined the same thing, except in human saliva, which naturally has much more moisture available than the airways. They used both healthy samples and samples from people with cystic fibrosis.
Then they examined mucins produced by pigs, using cell cultures from domestic pig tracheas. To simulate cystic fibrosis, they inhibited the production of chloride ions in the experimental group, thereby dehydrating the samples.
People with cystic fibrosis, whether or not the samples were taken two minutes or four hours, showed no shift in their MUC5B from a compact state to an open state. Healthy people’s mucus proteins for the most shifted position and opened up, with only a little bit staying compact. Both groups had an equal initial amount of mucin excreted.
That was basically validation of previous research. Onto the new findings.
The more hydrated saliva samples showed that the mucins opened up in both groups, though one third of the mucus in the cystic fibrosis samples still held compacted mucins. One third of the mucins stayed closed, which is still much better than all of the mucins from the airways of people with cystic fibrosis.
In the pigs, the control group showed a normal amount of unfolding, while the experimental group with its chloride inhibition kept the mucins compact and dense.
In both the cystic fibrosis group and the pig mucus in which chloride ions had been inhibited, some of the mucins produced even more compact and adhesive clumps than when they had been secreted. When exposed to the highly hydrated environment of saliva, these extra viscous clumps were basically the only maladjusted mucins left. All of the rest had unfolded properly.
Discussing the Results
Basically, when the mucins are exposed to a more hydrated area, they unfold more completely. So, while cystic fibrosis does affect the creation of MUC5B, it also affects the maturation of the protein, and that maturation may cause more of the negative symptoms of cystic fibrosis than the initial mutation causes.
This extra knowledge may not seem like much, but it can potentially lead to therapies which can help patients of cystic fibrosis breathe more easily.
In fact, two potential therapies have been suggested, and one is already being tested.
So, if dehydration of the airways is a major contributor to the extra thick and viscous mucous of people with cystic fibrosis, is hydrating those airways the way to go?
Drinking more water will not help. The lack of chloride ions, those tiny water pumps, ensures that excess water will not make it to where it needs to go. However, there is another way. Applying the water externally.
Sterile saline water, inhaled and thus exposed to the airways from the outside, has been shown to hydrate those airways and thin the mucus. This has helped people combat their declining lung function.
Do not take this as a suggestion to run out and try to breathe ocean spray. The clinical studies are still underway, and the best methods of applying the saline are still being examined. Breathing water improperly itself can impair lung function, and you do not want to stack that on top of viscous mucus.
The other potential therapy is to develop a drug which can target the chemical bonds between the mucin proteins, breaking them apart immediately after secretion. Even without hydration this will thin the mucus, and combined with a hydrating saline spray, may be able to greatly improve the ability of people with cystic fibrosis to breathe.
Many different factors come together in patients with cystic fibrosis to thicken their mucus and keep it extra viscous. But most of the problem may come from a lack of water, and now that the issue is known, therapies to improve your quality of life are already being developed.