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.

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

Allergy sufferers are breathing a sigh of relief with the news that FDA-approved medications taken via a pill or drops under the tongue over the course of weeks – as opposed to a series of injections that might last years – are starting to hit the market.

The sublingual medication is as effective in some patients as injections, a standard course of treatment that has changed little in the past 100 years, said Richard F. Lockey MD, FACP, professor and director of the Division of Allergy and Immunology in the USF Health Morsani College of Medicine and holder of the Joy McCann Culverhouse Chair of Allergy and Immunology.

“Sublingual immunotherapy has been around for a long time but earlier concentrations were ineffective because they were in too small of doses to help patients build immunity,” Dr. Lockey said. “These new standardized pills and drops are now in larger doses and have proven to be as effective in double-blind, controlled studies. These properly balanced studies showed a statistically significant benefit to patients.”

The first pills and drops available this summer target certain grasses and ragweed. Formulas for cat, dust mite and other allergens should be available next, Dr. Lockey said, while those for oak, Bahia and Bermuda grasses, other trees, weeds and molds may take years.

On-going clinical studies play into the pace for when the new sublingual immunotherapies become available. USF Health is a clinical site for the study related to dust mite allergies and continues to seek people allergic to dust mites to participate in the study, Dr. Lockey said. For more information about the dust mite study, call (813) 631-4024.

The number one allergen for Floridians is oak, Dr. Lockey said, so local allergy sufferers will have to wait because it is not yet a standardized allergen and not available for sublingual immunotherapy.

Patients who might benefit from the new medications are those who are allergic to only one or two things, and only seasonally. Those allergic to multiple things, called polysensitized, would likely see bigger benefits from shots, Dr. Lockey said. That’s because the serum used for injections can include concentrations for multiple allergens, creating a medication that is tailored to match each patient’s allergies. The new sublingual immunotherapies target only single allergens, making them somewhat like “one-hit wonders.”

But it also depends on where the person lives, he said. For example, people allergic to ragweed might be a candidate for the sublingual medications if they live up north, where ragweed blooms only seasonally. If they live in Florida, where ragweed is a year-round bloomer, they would not be prescribed the sublingual option.

The advantages for the new sublingual pills and drops are significant for patients, Dr. Lockey said, with time savings being the greatest. Sublingual immunotherapies are taken for about 12 weeks before the season begins and during the season for a patient’s particular allergen, he said. Injections are typically given one or two times each week for three to five months and monthly thereafter for three to five years or more. In addition, sublingual medications can be self-administered once the patient has taken the first dose at a physician’s office to monitor for adverse reactions. Injections require a visit to the physician’s office.

One of the big hopes, Dr. Lockey said, is that the new easy-to-take medications might entice more people to find relief.

“Some patients cannot pursue shots because of time constraints,” he said. “Sublingual immunotherapies can be given at home.”

For more information about the new sublingual immunotherapies and to make an appointment with a USF Health allergist, call (813) 974-2201.

Photos by Eric Younghans, USF Health Office of Communications