It is widely believed that asthma is triggered by changes to airway structure that arise from an inflammatory response to allergens. In a new report, however, researchers challenge this notion, finding that such changes may instead be prompted by a “rogue” gene.
The researchers – led by Hans Michel Haitchi, associate professor in respiratory medicine at the University of Southampton in the United Kingdom – suggest that blocking this gene, called a disintegrin and metalloprotease 33 (ADAM33), could halt asthma development.
They recently published their findings in The Journal of Clinical Investigation.
According to the Centers for Disease Control and Prevention (CDC), around
Popular notion holds that asthma is provoked by inflammation of the airways in response to asthma “triggers,” which may include airborne allergens and pollutants, such as pollen, mold, and smoke.
Studies have suggested that this inflammatory response plays a causal role in airway remodeling – structural changes such as an increase in smooth muscle mass and blood vessels in the airways, which are characteristics of asthma.
However, in their study, Prof. Haitchi and his team suggest the gene ADAM33 is responsible for both airway remodeling and inflammation – a discovery that they say raises questions about current understanding of asthma.
It was already known that ADAM33 plays a role in asthma; previous research has shown that people who possess this gene are at increased risk of the respiratory disease.
However, Prof. Haitchi and colleagues note that little is known about the specific mechanisms by which ADAM33 may contribute to asthma development.
In their report, the researchers reveal the results of a number of studies they conducted that aimed to shed light on such mechanisms.
The team explains that ADAM33 produces an enzyme that binds to cells in the muscles of the airways. If the enzyme loses its grip on a cell, it can travel to the lungs, where it can impair the organs’ functioning.
By studying human tissue samples and mice, the researchers found that the enzyme produced by ADAM33 is a trigger for airway remodeling; specifically, they found the enzyme increased smooth muscle mass and blood vessel formation in the airways of developing lungs. This enzymatic activity alone, however, did not trigger inflammation.
However, when mice with the ADAM33 gene were exposed to household dust – a common asthma trigger in humans – the team found that this led to an increase in both airway remodeling and inflammation, suggesting that asthma development requires both the ADAM33 gene and an inflammatory response to allergens.
To further investigate this hypothesis, the researchers activated ADAM33 in mice in utero. They found that this triggered airway remodeling, but when the gene was deactivated, airway remodeling was reversed.
Additionally, when mice without the ADAM33 gene were exposed to house dust, they found that airway remodeling and twitchiness – or hyperresponsiveness – reduced by 50 percent, while airway inflammation reduced by 35 percent.
These findings, say the researchers, suggest that blocking ADAM33 could halt asthma development.
“Our studies have challenged the common paradigm that airway remodeling in asthma is a consequence of inflammation. Instead, we have shown that rogue human ADAM33 initiates airway remodeling that promotes allergic inflammation and twitchiness of the airways in the presence of allergen.
More importantly, we believe that if you block ADAM33 from going rogue or you stop its activity if it does go rogue, asthma could be prevented. ADAM33 initiated airway remodeling reduces the ability of the lungs to function normally, which is not prevented by current anti-inflammatory steroid therapy.”
Prof. Hans Michel Haitchi
Dr. Samantha Walker, director of research and policy at Asthma UK, reveals the charity has agreed to fund the next stages of the team’s research, which she describes as a “promising avenue” to uncovering ways to halt asthma, rather than just treating its symptoms.