Mucus-plugged airways marked by prominent airway remodeling in patients with asthma

Key takeaways:

• Airways with mucus plugs have thicker epithelium, basement membranes and smooth muscle than unplugged airways.
• These thicker features occur in patients with fatal and nonfatal asthma alike.

WASHINGTON — Airways plugged with mucus experience more remodeling than airways that have not been plugged with mucus among patients with asthma, according to data presented at the American Thoracic Society International Conference.

But although this remodeling occurs throughout the airway wall, it is not uniform, Aileen Hsieh, MS, PhD candidate, Hackett Lab, UBC Centre for Heart Lung Innovation, University of British Columbia, and colleagues wrote.

“Airway remodeling in asthma is a main contributor to fixed airflow obstruction and is associated with increased frequency of exacerbations,” Hsieh said during her presentation.

Asthma remodels the epithelium in asthma, Hsieh explained, as a thickened reticular basement membrane, increased smooth muscle mass, subepithelial fibrosis and goblet cell hyperplasia cause mucus to accumulate in the lumen.

The Severe Asthma Research Program investigated severe airway remodeling among 164 patients with severe asthma over the course of 3 years, including asthma plugs that persisted in the same airway from baseline through the study period.

Spatial examinations found that bronchopulmonary segments that were plugged at baseline tended to remain plugged 3 years later.

“This really tells us that these mucus plugs are persisting in the same airways over time,” Hsieh said.

There was a negative association between changes in FEV₁ percent predicted and changes in mucus plug scores as well, indicating that mucus plugs may be a mechanism behind airflow obstruction and that worse clinical outcomes occur among patients with mucus plugs, Hsieh said.

“As we know that mucus plugs are a persistent and consistent airway remodeling feature, we now want to understand how they are formed and, importantly, why they persist over time,” she said.

Clinical computer tomography (CT) did not allow the researchers to answer these questions, Hsieh said, so they examined whole lungs from eight healthy controls (five females; average age, 20.5 years), five patients with nonfatal asthma (three females; average age, 26.4 years), and nine patients (five females; average age, 14.67 years) who died of asthma.

With each airway measuring less than 2 mm in diameter, the researchers assessed 115 airways overall, including 22 in the control group, 40 in the nonfatal asthma group and 53 in the fatal asthma group.

During the CT of each specimen, the researchers identified a mucus plug and then registered the image to a lung slice, enabling them to take the exact tissue core that they wanted.

The researchers next scanned the tissue core with micro-CT to obtain an ultra-resolution image, Hsieh said. Finally, the researchers stained these slices for histological images of the airway that they used to confirm the presence of the mucus plugs.

Meanwhile, the researchers also used Euclidian distance mapping to manually segment these features and generate binary masks to reveal the total wall, the epithelium, the basement membrane and the smooth muscle of these airways.

“We then perform local thickness analysis, which create these colorful distance maps that work by fitting maximal circles to every point within the airway remodeling feature,” Hsieh said.

The study confirmed that patients with asthma have thickened airway walls, which has been established since the 1920s, Hsieh said. In their study, the researchers found that the fatal and nonfatal asthma cases both had thickened airway walls.

“When we look at each airway remodeling feature, we see that the epithelium, the basement membrane and the smooth muscle are all thickened in nonfatal and fatal asthma,” Hsieh said. “So, our remaining question really was, ‘Are there differences in airway remodeling features in mucus-plugged vs. nonplugged airways in asthma?’”

The mucus-plugged airways had significantly thicker epithelium compared with the unplugged airways, Hsieh said, possibly because of the extent of goblet cell hyperplasia happening in the epithelium leading to the thickening.

Similarly, the basement membrane in airways with mucus plugs were significantly thicker than the basement membrane in the unplugged airways, she continued.

“This is interesting because we know that basement membrane remodeling is known to predict asthma severity and exacerbations and is also present in all asthma patients,” Hsieh said.

Airways with a mucus plug had significantly thickened smooth muscle as well.

“This is important because we’ve known for a long time now that smooth muscle mass is what’s really responsible for the bronchoconstriction that occurs,” Hsieh said.

Overall, the mucus-plugged airways in patients with fatal and nonfatal asthma alike were more remodeled than the nonplugged airways in the same patient, the researchers concluded.

“We believe that this may help us to identify a mechanism for how remodeled airways lead to heterogenous airflow trapping,” Hsieh said.

Next, Hsieh said, the researchers will focus on understanding the mechanisms of how mucus plugs form, how they persist and relate to T-helper 2 cell information, and how treatments may target them.