January 17, 2023—In this Big 3 Q&A, Ronald Panganiban, research scientist in the Department of Environmental Health at Harvard T.H. Chan School of Public Health, discusses a recent paper he co-authored with Quan Lu, Cecil K and Philip Drinker Professor of Environmental Physiology, and other colleagues, that identifies a mechanism behind obesity-related asthma—and existing compounds that could be re-purposed to treat it.
Q: Why did you focus on obesity-related asthma?
A: Obesity-related asthma is poorly understood and very difficult to manage. In general, it is different from conventional allergic asthma and exercised-induced asthma, but certain clinical features are shared between them. One is airway hyperresponsiveness—meaning that the airway narrows in response to a trigger, which causes difficulty breathing.
Obesity is both a risk factor and a disease modifier for asthma, in that obesity increases the risk of developing asthma and asthma patients with obesity tend to have more symptoms and more exacerbations, and do not respond well to several standard asthma medications.
Currently, these patients’ symptoms are managed using the same pharmacologic treatments used for asthma patients who are not obese—for example, a quick relief rescue inhaler and an anti-inflammatory corticosteroid—but they are typically less effective, decreasing patients’ quality of life.
Q: What is the mechanism you identified?
A: We found that a hormone called cholecystokinin contributes in part to the airway narrowing that results in airflow limitation in obesity-related asthma. When we blocked the action of this hormone, we were able to improve airflow in the lungs of obese mice.
Although the function of cholecystokinin as a gut and brain hormone has been known for a long time, its function in the lung has not been well-described. Previous studies have suggested that this hormone, along with its receptor CCKAR, might be involved in narrowing of the airways, but the story was not complete.
We now provide evidence that cholecystokinin and CCKAR are involved in obesity-induced airway narrowing. The mechanism behind obesity-related asthma has been poorly understood, so this is a big step in the research.
Q: And you uncovered a potential new treatment pathway?
A: Yes, we found that existing pharmacological compounds that block CCKAR, known as CCKAR antagonists (proglumide, lorglumide, and devazepide), could lower asthma symptoms in obese mice. These compounds were originally intended to be used for other diseases such as stomach ulcers. They are generally safe to use without dangerous adverse effects. If our study is replicated in humans, we can then potentially use these compounds to treat asthma in people with obesity.