Researchers from Harvard University in Cambridge, MA, have developed a model that they say accurately simulates muscle contraction in the human airway, providing a tool to test new drugs to treat asthma.
The research team, led by Alexander Peyton Nesmith, a student at the School of Engineering and Applied Sciences at Harvard, publish the details of their creation in the journal Lab on a Chip.
Asthma affects more than 300 million people worldwide and is responsible for around 250,000 deaths every year. It is also a leading cause of emergency room visits and hospitalization among children.
There are a number of medications that can help asthmatics manage their condition, such as inhaled corticosteroids and beta-agonists. But according to the researchers, many of these medications are more than 50 years old. In the last 30 years, the Food and Drug Administration (FDA) have only approved two new drugs to treat asthma.
“Unfortunately, many patients remain resistant to these treatments and are at greater risk for exacerbation,” say the researchers. “This suggests an emergent need to accelerate the pipeline for discovery and validation of airway drugs.”
Nesmith and his team note, however, that finding new treatments for asthma is challenging. New drug candidates are usually tested in animal models, but these models may not mimic human responses so the drugs often fail in clinical trials. Furthermore, because the disease is specific to each patient, treatments that work for one individual may not necessarily work for another.
“Hence,” the researchers say, “we sought to develop a robust, functional, human-relevant model that can be used for screening new therapies against asthma.”
A ‘simple, reliable and direct way’ to measure human response to asthma triggers
The human airway is made up of layers of smooth muscle that contract and relax to decrease, then increase its diameter.
Fast facts about asthma in the US
- Asthma affects 1 in 12 people in the US
- In 2008, more than 50% of people with asthma had an asthma attack
- Between 2008 and 2010, asthma prevalence was higher among children than adults.
The team built what they describe as an “airway muscular chip” mounted on a glass substrate.
The chip is made up of human bronchial smooth muscular thin films (bMTFs). These consist of a bottom layer of elastic polymer polydimethylsiloxane (PDMS) and a top layer of engineered bronchial smooth muscle. “When the muscle layer contracts, the bMTF bends, reducing the radius of curvature of the tissue,” the researchers explain.
To test the model’s effectiveness, they introduced a protein called interleukin-13 (IL-13), which is commonly found in the airway of patients with asthma. It is known to trigger the smooth muscle’s response to allergens. The team then added a neurotransmitter called acetylcholine, which causes contraction of smooth muscle, to induce an allergic response.
They found that high doses of acetylcholine caused the airway muscle on the chip to hypercontract. When the team introduced beta-agonists to the chip – used in inhalers to reduce airway inflammation – the airway muscle relaxed.
The researchers note they were able to measure the muscle tissue’s contractile stress in response to different drug doses. “Our chip offers a simple, reliable and direct way to measure human responses to an asthma trigger,” says Nesmith.
Investigating cellular and protein responses to IL-13
According to the researchers, thickening of bronchial smooth muscle in the airway wall is a structural characteristic of asthma, causing the airway to narrow. Using the airway muscular chip, the team wanted to see whether IL-13 induced such a response on a cellular level.
They found that IL-13 caused an enlargement in smooth muscle cells, and in addition, modified the organization of actin fibers in these cells – cellular components that play a role in muscle contraction.
The team then wanted to see how IL-13 modified the expression of RhoA proteins. Past research has indicated that these proteins are involved in regulating bronchial smooth muscle contraction, but the underlying mechanism has been unclear.
After introducing a drug that targets the RhoA pathway, called HA1077, the researchers found that it made the tissue on the chip that was exposed to IL-13 less sensitive to asthma triggers. “This result indicates HA1077 decreases the basal tone of our engineered bronchial smooth muscle tissue and prevents hypercontraction,” the team explains.
Further investigation revealed that HA1077 combined with an already existing asthma drug, isoproterenol, was more effective in reducing response to asthma triggers than isoproterenol alone. This means the airway muscular chip has already shown promise in identifying a potential new asthma treatment.
Commenting on the team’s creation, Donald Ingber, a professor or bioengineering at Harvard’s School of Engineering and Applied Sciences and founding director of the Wyss Institute at the university, says:
“Asthma is one of the top reasons for trips to the emergency room, particularly for children, and a large segment of the asthmatic population doesn’t respond to currently available treatments.
The airway muscle-on-a-chip provides an important and exciting new tool for discovering new therapeutic agents.”