New Study May Explain Mucus Issues in People with CF

As someone with cystic fibrosis, you probably sometimes have difficulty breathing. You may even know that the cause of the trouble most often relates to the mucus in your lungs. It is a clear, green or yellow slime which causes intense aggravation. In the case of people with cystic fibrosis, it can endanger their life. So why does your body produce it, anyways? And why does it seem like people with cystic fibrosis have mucus that hurts them from the inside?

What is mucus and what does it do?

Mucus is a viscous colloid, which means it is a mixture of many substances suspended in another substance. Being viscous, it sticks together. Though mostly water, it contains many other parts as well. Sodium and potassium ions hang out in the slime. Mucin, a glycosylated protein (protein bit with a carbohydrate bit attached), is responsible for the gel-like qualities of mucus.

Being mostly water and a carrier of inorganic salts such as sodium ions, mucus helps manage your interior cells’ hydration levels. It also provides a lubricant effect to prevent friction from damaging internal parts of you when they rub together. Mucus helps the immune system as well. It accomplishes this in two main ways, physical protection and by carrying substances which act on behalf of your immune system. As a viscous gel, physical intruders such as fungal spores and allergens get caught in the slime. Cilia, tiny hairs lining your airways, then expel the compromised mucus.

As for being an extension of the immune system, mucus contains many parts. Glycoproteins such as lactoferrin (which is also found in milk) render the mucus inhospitable to bacteria and fungi. Enzymes such as lysoenzyme are suspended as well, which are also antiseptic as they damage the cell wall of bacteria. Immunoglobulins, commonly known as antibodies, neutralize bacteria and viruses known to be hostile to your body.

When a good thing goes bad

With all the good mucus does for your body, there is still the potential for it cause negative effects. The lungs do not clear themselves properly of mucus. Keeping the bacteria, fungal spores, and viruses inside the lungs can allow them to establish themselves and cause an infection. Inflammation can also result.

One of the ways this goes wrong is the epithelial sodium channel, also known as ENaC, the pathway in which sodium enters and leaves the cells of your lungs. In people with cystic fibrosis, ENaC becomes hyperactive. This causes the sodium and water balance to go awry, and much more mucus than necessary is produced, clogging the lungs and airways with the slime. Extra mucus is not the end of the matter, however. Otherwise decongestants and expelling extra mucus would be all that’s required to keep airways clear. Some researchers noticed that the mucus itself was different in people with cystic fibrosis as opposed to people without the disease.

The new study

Researchers at the University of Iowa published their study in Proceedings of the National Academy of Sciences Early Edition. The team was led by Michael J. Welsh, MD, the director of the UI Pappajohn Biomedical Institute, professor of internal medicine in the UI Carver College of Medicine, and a Howard Hughes Medical Institute investigator. All the same person.

He was joined by Lynda S. Ostedgaard, PhD, UI research associate professor of internal medicine. Other research in the study included Thomas O. Moninger, James D. McMenimen, Nicholas M. Sawin, Connor P. Parker, Ian M. Thornell, Linda S. Powers, Nicholas D. Gansemer, Drake C. Bouzek, Daniel P. Cook David K. Meyerholz, Mahmoud H. Abou Alaiwa, and David A. Stoltz.

The study is titled Gel-forming mucin form distinct morphological structures in airways. They looked into two specific mucins, gel-forming glycosylated proteins produced by lung and airway tissue. The two mucins in question were MUC5B and MUC5AC. They exposed airway tissue and examined the mucus directly. To mark MUC5B they used wheat germ agglutinin, and to mark MUC5AC they used jacalin lectin.

MUC5B is produced by submucosal glands, which means that the glands themselves are below the lining of the internal part of your body. MUC5B typically forms strands as it is excreted. MUC5AC is produced by goblet cells, which are scattered throughout the lining of your lungs and airways. MUC5AC is typically secreted in the form of small threads or thin sheets. Together, the MUC5AC sheets cover the MUC5B threads. They work together to capture inhaled particles and are moved by the cilia to be expelled.

However, in pigs with cystic fibrosis, the mucin proteins are not formed properly. MUC5B strands tangle together and do not properly detach from the ducts of the submucosal glands. MUC5AC sheets are larger and produced in a higher quantity. Pigs with cystic fibrosis have the same symptoms as humans with the disease and their mucus is produced in the same way as humans, unlike the standard laboratory animal, mice.

Though it is known that mucins are important to the function of mucus, a clear understanding of precisely what the mucins did had not yet been established. Few studies looked at the physiology of mucus on lung and airway cells. In a petri dish, mucus has nowhere to flow and behaves differently, so it was important they examined mucus fresh on the airways.

After observing the difference in mucin formation between pigs with cystic fibrosis and those without, the researchers went on to test a hypothesis about what may have contributed to the change. They inhibited chlorine and bicarbonate secretion in airway cells of a pig without cystic fibrosis using a solution of saline and bumetanide. The glands filled with mucus from MUC5B as if the animal had cystic fibrosis. This last part was in line with earlier studies, that changing the ion concentration of the mucus affected further mucus development, but was still important as it showed that their method of marking the mucins MUC5B was effective.

The study does not present all of the answers as to what leads to MUC5AC causing trouble, however. The two main hypotheses are either that cystic fibrosis leads to more MUC5AC sheets to be produced, or perhaps the sheets may be produced the same as in people without cystic fibrosis but get caught by stationary MUC5B strands. Other possibilities are, well, possible. The researchers pointed out that there are other unstudied ways in which mucus might be thicker for people with cystic fibrosis. This study looked at mucins, but mucus also contains other proteins, lipids, and sugars. Any of those may contribute as well. The researchers are already looking to study the subject more in the future.

Grants from the National Heart, Lung and Blood Institute, the Cystic Fibrosis Foundation, and the Roy J. Carver Charitable Trust helped fund part of the research.

The bottom line

Science continues its march ever forward, and with this study we know a little more about what causes some difficulties suffered by people with cystic fibrosis. Though this research has no direct impact at the moment, the greater understanding of the biophysical properties of the mucus will allow other researchers to attempt to develop medicine to allow mucins to be produced correctly.

This will allow that medicine to strike the source, rather than mask the symptoms. It is always more effective to heal the cause rather than treat the symptom, so this study has potential long-term positive implications for people with cystic fibrosis.