People with cystic fibrosis have thick, sticky mucus that blocks passages in their lungs, making it difficult for them to breathe and predisposing them to infections. New drugs are under development that will help break up and hydrate mucus in the lungs to make it easier to clear. 

How Does Mucus Affect the Lungs of People With CF?

Mucus is essential in the lungs, where it traps germs and pollutants that we inhale. Tiny hairs on the outside of cells, called cilia, propel the mucus out of the lungs and into the throat where the mucus can be swallowed or coughed out.

In people with cystic fibrosis, mucus is dehydrated, becoming so thick and sticky that the cilia are unable to propel mucus out of the lungs. As a result, the mucus clogs the airways, making it difficult to breathe. Because the mucus in people with CF is also abnormal in other ways, it is less able to kill germs than the mucus in healthy people, creating a fertile breeding ground for infections.

Why Does Mucus Build Up in the Lungs?

In people with CF, mucus becomes thick and sticky because of problems with the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The CFTR protein normally forms a channel to transport chloride -- a component of salt -- through the membranes of cells lining many surfaces in the body, including the surface of the lung. When the protein is not working correctly or is not present at the cell surface, chloride becomes trapped in cells and cannot attract the fluids necessary to hydrate the cell surface. Without the fluids, mucus becomes dehydrated and takes on a thick, sticky consistency.

This animation depicts how mucus builds up in the lungs of people with cystic fibrosis.

Researchers believe another protein channel on the surface of the cell adds to this hydration problem. This channel, known as the epithelial sodium channel (ENaC), absorbs sodium (another component of salt) into the cell, which also helps to maintain the correct balance of salt and fluids on the cell surface. In people with CF, researchers think the sodium channel is hyperactive and takes in too much salt. Thus, this overactive channel contributes to the dehydration problem in the airway.

What Research Is Being Conducted?

To advance the development of new treatments, scientists are studying how mucus is secreted normally to identify how to restore its proper consistency and germ-fighting qualities in people with CF. They are researching the following:

  • How mucus affects the airway
  • Why mucus is abnormal in CF
  • Where mucus is most important
  • How the properties of mucus affect its structure
  • Why CF mucus is more prone to infection

Scientists also are conducting research on how much liquid covers the cells lining the airways and what factors contribute to airway hydration. In addition to the chloride and sodium channels, researchers are examining the role that calcium-activated chloride channels (CaCC) have in hydrating mucus and whether these channels could be stimulated to improve the flow of fluids in the airways.

What Treatments Are Being Developed?

Researchers are evaluating drugs for their effectiveness in preventing, thinning, and breaking up the mucus in the airways. These drugs include CFTR modulators, ENaC inhibitors, CaCC activators, and mucolytics (mucus thinners).

By restoring function to the CFTR protein, CFTR modulators help restore the flow of chloride out of the cell and prevent mucus from becoming dehydrated, making it easier for people with CF to clear their lungs. Early clinical trial results have indicated the triple-combination modulators will likely be more effective than current modulators and could potentially treat a much larger population of people with CF.

Researchers also are working on drugs that are mutation-agnostic, which means they can help all people with CF regardless of their mutations. One such drug would prevent mucus from becoming dehydrated, inhibiting the hyperactive ENaC to enable more salt on the cell surface. The salt would then attract fluids, hydrating the mucus. Several ENaC inhibitors are under development in clinical trials.

In this video, Scott H. Donaldson, M.D., associate professor of medicine and director of the adult CF center at the University of North Carolina, talks about ENaC inhibitors and other approaches being explored to improve mucociliary clearance.

What Current Treatments Do We Have?

For more information on current treatments, visit Medications.

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