“Bronchi on a chip” could lead to better therapies for difficult-to-treat asthma

A collaborative team, including USF Health’s Dr. Stephen Liggett, uses the new airway model to analyze the mechanisms of bronchial spasms

A subset of patients with asthma – about 20 percent – suffer a degree of persistent airway constriction that does not respond well to traditional medications. In the worst cases, patients with difficulty breathing require visits to hospital emergency departments for rescue medications and intensive treatment with oral corticosteroids.

Now a collaborative team, led by researchers at Johns Hopkins University and Yale and including a physician-scientist from the University of South Florida, has created a microdevice simulating the behavior of bronchial airways to investigate why it is so difficult to successfully treat some asthma patients.  The team expects the new technology to be applied to drug screening and discovery, and may lead to improved treatments for asthma and other obstructive lung diseases.

Their findings appeared recently in Nature Biomedical Engineering.

Known as “bronchi on a chip,” the microphysiological model allows researchers to better analyze the mechanisms of bronchial spasms, sudden contractions of the smooth muscles surrounding bronchial tubes that deliver oxygen to the lungs. Like breathing through a pinched straw, bronchospasm leads to decreased air flow in asthma patients.

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USF Health’s Dr. Stephen Liggett was a member of the collaborative team using a new airway microdevice to study why it is so difficult to successfully treat some asthma patients.

Asthma research is challenging because mouse models do not adequately replicate the features of human asthma and existing laboratory models using human lung tissue are unstable, said study co-author Stephen Liggett, MD, vice dean for research, and professor of internal medicine, molecular pharmacology and physiology, and medical engineering at USF Health Morsani College of Medicine.

“This airway model gets us closer to the human condition than ever before,” Dr. Liggett said.  “It demonstrates the interactions between mechanical activity, like the pressure on the bronchial airways caused by a cough, and the biochemical signals created by that mechanical stimulus.”

The silicone-polymer microdevice incorporates both human epithelial cells lining the bronchial airway, which compress in response to bronchospasm, and strips of smooth muscle cells surrounding the airway.  The model can be manipulated to more precisely measure what happens when the compressive stress applied to epithelial cells changes and resulting smooth muscle cell contractions are altered. The researchers record the twisting motion of magnetic beads attached to the smooth muscle cells’ surface to monitor mechanical changes within the cells when muscles contract and relax.

Graphic courtesy of Steven S. An

Among the team’s discoveries using the experimental model:

–  Increased airway compression (mechanical stress) mimicking severe bronchospasm deforms epithelial cells, causing them to release chemicals that stimulate airway smooth muscle contraction.

– Bronchospasm, triggered by allergens (like dust mites or pet dander) or other irritating substances (like smoke), represents a “wave” of signals rather than a single set of triggers.

-For severe asthma, the feedback interaction between smooth muscle and epithelial cells could be strong enough to promote relatively recurrent or persistent bronchospasm – even when the environmental trigger is removed.

-A protein with a mechanosensor function (yes-associated protein or YAP) helps regulate signaling between bronchial epithelial and smooth muscle cells and enables the epithelial cells to sense airway mechanical stress.

“The model helps explain how difficult-to-treat asthma becomes a (feedback) cycle sustaining a constricted airway state that is difficult to break,” Dr. Liggett said.

Illustration of the “bronchi on a chip” airway model used to analyze bronchial spasms. Regulated air pressure applies compressive stress to bronchial epithelial cells at varying levels, and the device precisely measures resulting changes in airway smooth muscle (ASM) cell contractions. The twisting motion of magnetic beads monitors mechanical changes within the ASM cells when muscles contract and relax. | Graphic courtesy of Steven S. An