Unplugging asthmatic airways

Blessing Azeke wrapped her cardigan around her body as another asthma attack set in. Provoked by cold air from an overhead fan in her law school classroom in Enugu, Nigeria, her lungs refused to let her breathe. The attack made Azeke so weak that she could hardly move on her own. She was rushed to the school’s clinic yet again.

For Azeke and more than 260 million other people with asthma worldwide, such attacks are a constant threat. Cold air, allergens and other triggers cause inflammation in their lungs, narrowing the air passages and increasing mucus production. Often, plugs of mucus block smaller airways completely, and this obstruction is a major cause of the nearly half-million deaths caused by asthma each year.

Coping with severe asthma like Azeke’s can be tricky because existing therapies don’t treat all facets of the disease. Anti-inflammatories such as corticosteroids reduce inflammation and swelling in the airways, but they don’t prevent excessive mucus secretion or clear existing mucus plugs from the lungs. And therapies targeted at clearing airway mucus do not reduce inflammation and barely reduce the overactive secretion of mucus or dissolve plugs in the airways.

Today, researchers are working on several promising new treatments to prevent or clear mucus plugs that may leave people with asthma breathing easier.

At the heart of the problem is mucus itself, a viscous mixture of water, cellular debris, salt, lipids and proteins that performs the crucial job of trapping foreign particles and ferrying them out of the lungs. The primary component of this fluid is a family of proteins known as mucins, which give mucus its gel-like thickness. In people with asthma, genetic changes in mucin proteins make the mucus thicker and harder to clear from the lungs.

When that happens, allergens, pollutants and pathogens can accumulate in the lungs, triggering inflammation that leads to further mucus secretion as the body works to rid itself of the threats. The result is the accumulation of airway-blocking mucus plugs.

Currently, doctors treat mucus plugs with inhalable medications such as bronchodilators to widen airways, corticosteroids to reduce inflammation to enable the easier flow of mucus, and drugs called mucolytics that break down the mucins themselves.

However, the only available mucolytic, known as N-Acetylcysteine (NAC), is not very effective at breaking the bonds in mucin. And at high doses, it can cause cough and raise the risk for bacterial pneumonia and other adverse side effects. “It’s very rarely used because its activity is very, very weak and people have to take very high doses of it to get effects,” says Christopher Evans, a pulmonary scientist at the University of Colorado Anschutz Medical Campus who studies how airway mucins regulate respiratory health and diseases.

To address this shortcoming, Evans and others are trying to discover more effective mucolytics to dissolve mucus plugs. He and his team recently tested a different bond-breaking agent, similar to NAC but much more potent and effective at breaking up mucus plugs.

In their studies, the researchers exposed mice to a fungal allergen once a week for four weeks. This stimulated inflammation and mucus overproduction, mimicking a full-blown asthma attack. Then they treated the mice with a mucolytic agent known as tris (2-carboxyethyl) phosphine. The treatment improved mucus flow, the team found, allowing the asthmatic mice to clear mucus just as well as mice that had not been exposed to the allergen, with higher doses yielding better results.

Evans cautions that the bonds that hold mucins together are also found in other proteins, so the risk of side effects is high. Finding a drug that will break bonds only in mucins, he says, “is still pretty far from reality at this point.”

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Clearing crystals

In a different approach to the problem, immunologist Helena Aegerter of Ghent University in Belgium and her colleagues are focusing on what they believe drives mucus overproduction in asthma: protein crystals called Charcot-Leyden crystals (CLCs) that form as byproducts of dead white blood cells called eosinophils. The presence of these crystals in mucus makes it thicker and more challenging to clear from airways.

Other researchers had already shown that these crystals induce inflammation in the lungs by recruiting immune cells. And earlier work by Aegerter and colleagues showed that the crystals enhance mucus production in mice with chronic asthma. Perhaps, she thought, dealing with the crystals could be the best way to avoid the formation of mucus plugs. “You can target mucus and you can target inflammation, but while you still have these crystals in the airways, they are always going to drive a vicious cycle of mucus production and inflammation,” says Aegerter, who coauthored an article on the pathology of asthma in the 2023 Annual Review of Pathology: Mechanisms of Disease.

To address the crystals directly, Aegerter and her colleagues developed antibodies in llamas, then engineered them to more effectively attack the proteins in the crystals. They then tested them on mucus samples collected from people with asthma. The antibodies successfully dissolved the crystals by attaching to specific regions of the CLC proteins that hold the crystals together, the team reported in 2022. The antibodies also neutralized inflammatory reactions in mice. Based on these findings, the scientists are working on a drug that would have the same effect on people.

“Our strategy, now, is really to target the crystals at the heart of the mucus plug. And by getting rid of the crystals, hopefully, that will put a stop to all the mucus production and inflammation that happens around these airways,” says Aegerter. The approach could work not just for asthma, she says, but also for a variety of other inflammatory diseases involving mucus oversecretion, such as inflammation of the sinuses and some allergic reactions to fungal pathogens.

Taming the flow

In a third approach, pulmonologist Burton Dickey of the University of Texas MD Anderson Cancer Center is working to avert mucus plugs by preventing excess secretion of mucus. After 20 years of work on airway mucin secretions, Dickey’s team published a paper in 2022 identifying a protein, synaptotagmin 2 (Syt2), that is involved in the excessive mucus secretion experienced by people with asthma and other conditions.

Dickey and his team induced mucus overproduction in mice by exposing their airways to an inflammatory molecule called interleukin-13. In mice lacking the gene for Syt2, they found, the IL-13 caused only normal mucus production in the mice’s lungs. In other words, it looked as if Syt2 was central to excess mucus production but had no role in normal mucus production, which is regulated by a different mechanism. That was promising: It suggested that a drug could be made to block excessive production only.

With this win under their belt, Dickey’s team next designed a molecule, which they called PEN-SP9-Cy3, that would block the action of Syt2 in inflamed lungs. When they tested this molecule on mice and on human cells in culture, they found that it significantly reduced the amount of mucins secreted.

One day, says Dickey, “we hope that when someone with a severe asthma attack comes to the emergency room they can breathe in our drug and it will prevent any further mucus plugging.”

In just six months during law school, Blessing Azeke had 10 emergency room visits. If any of these new approaches for treating asthma pan out, people like her can look forward to a future with fewer medical crises.

Editor’s note: The article was amended on February 16, 2023, to clarify that Christopher Evans works at the University of Colorado Anschutz Medical Campus.

Editor’s note: This story was updated on January 30, 2024, to add the subtitle to the name of the Annual Review of Pathology: Mechanisms of Disease journal.