Chronic asthma could be caused by cell overcrowding in the airways

Despite a wealth of available treatments to control the symptoms of chronic asthma, the lung disease has no cure. The discovery of an unexpected cause of asthma could change that.

A glitch in the mechanical process that drives normal turnover of epithelial cells lining the lungs could be to blame, researchers report in the April 5 Science. Better understanding of this physical force underpinning chronic asthma attacks might lead to new ways of combating the disease.

The mechanical process that drives epithelial lung cell turnover is called cell extrusion. It goes something like this: Epithelial cells in the lung lining replicate, and as new cells populate the tissue, things get crowded and pressure between the cells increases. Cells sense this crowding and initiate a process that ejects weaker cells from the layer, forcing them to die off. The process maintains a healthy epithelial lining in the airways.

There have been hints that this process could be implicated in asthma (SN: 9/26/18). But researchers studying the disease, which affects 300 million people worldwide and contributes to the death of 1,000 people a day, have focused on other triggers. In the early 1900s, the discovery that epinephrine could reverse shortness of breath led scientists to believe the disease was due to constriction of the smooth muscle surrounding the lungs. Decades later, scientists revised their understanding to include a problem with persistent inflammation in the airway.

After looking at images of lungs whose linings were riddled with damage from chronic asthma under the microscope, cell biologist Jody Rosenblatt had an epiphany. In 2015, she had published research showing the pressure from overcrowding in the epithelium could trigger cell death and extrusion. She wondered, could the pressure from a single asthma attack kick off a vicious cycle of cell death, damage to the lungs and future asthma attacks?

To test the hypothesis, she and colleagues first used methacholine, a drug that narrows the bronchioles, the tiniest airways lacing the lungs, to simulate asthma attacks in living mouse lung cells primed to be hyperresponsive. Fifteen minutes of constricting the airways caused severe crowding of epithelial cells and led to an excess of cells being ejected, with a strong correlation between the amount of constriction caused by the crowding and the sloughing of cells.

To see whether similar effects occurred in humans, Rosenblatt and colleagues obtained airway samples from people with moderate to severe asthma who were having lung cancer surgery. The patient samples showed severe extrusion, a buildup of mucus and immune cells, and damage in the airways, the team found.

“There was way too much extrusion, and the whole epithelium just fell apart,” says Rosenblatt, of King’s College London. “The damage itself can start to feedback, because you don’t have enough epithelium coating your airways [so] your lungs, stay contracted all the time trying to reduce [their] surface area.” The lungs will contract to maintain a barrier and keep allergens and irritants out.

Treatment of the mouse tissue with albuterol, a drug that relaxes the airways, did ease the constriction but did nothing to reverse the damage. As the mouse lung slices relaxed and the airways opened, there were more gaps in the epithelial lining, providing openings for allergens and irritants to get in. That may explain why people with asthma have noted that while albuterol helps with breathing, it feels like asthma can get worse over time, Rosenblatt says.

The research is “a gorgeous example of how the mechanics of the tissue contributes to the disease,” says Lisa Manning, a physicist at Syracuse University in New York who was not involved with the paper. She thinks physical forces play central role in human health and disease, though they are currently underappreciated. 

In another series of experiments, Rosenblatt’s team tested whether blocking cell receptors that sense mechanical force in mouse cells could prevent or reverse some of the damage from the excessive cell extrusion (SN: 10/4/21). The team targeted piezo1, a protein that senses the mechanical pressure of epithelial cell crowding, the first step in cell extrusion. After administering drugs that inhibited the receptor, the researchers observed a significant decrease in jettisoned cells, inflammation and mucus production, suggesting a way to prevent the damage.

These findings need to continue to be tested in mice and humans to see if there could be clinical applications.