Study identifies a new mechanism that causes airway hyperresponsiveness in asthma

Asthma is a condition in which a person’s airways turn hyperresponsive. Scientists from Uppsala University have identified a new mechanism that involves in, and explains, hyperresponsiveness of the airways. The findings of the study were published recently in Allergy, a scientific journal.

Asthma. Image Credit: Antonio Guillem/Shutterstock.com

Nearly 10% of Sweden’s population is affected by asthma. The airways in asthmatics become hyperresponsive, or overreactive, to different kinds of stimuli, like chemicals, cold air, and physical exertion. The airways turn constricted, which makes breathing hard.

Asthma is diagnosed through a “methacholine test” that is often used to identify whether a person exhibits signs of airway hyperresponsiveness. Methacholine binds to the so-called muscarinic receptors found in the smooth muscle cells that line the inner side of the trachea. Then, these muscle cells start contracting and cause constriction of the trachea.

As part of the new study, the team demonstrated that the airway hyperresponsiveness triggered by methacholine is partially due to the mast cells of the body. The study was performed by using a mouse model of asthma, where allergy to house dust mites was induced in the mice.

Mast cells are immune cells of a particular type belonging to the innate immune system. They are mainly found in tissues in contact with the external environment, for example, the skin and the airways.

Their location and the aspect that they contain several different receptors that can recognize parts of foreign or pathogenic substances enable them to react fast and become activated. Mast cells include storage capsules, called granules, in their cytoplasm. Some substances are stored inside these granules in their active form.

Upon activation of the mast cell, these substances can be quickly released and trigger a physiological reaction. This has a crucial role in the defense of the body against pathogens. However, in the case of asthma and other diseases, where the body starts reacting even against harmless substances in the environment, it turns out to be a problem.

As part of the study, the team could show that the mast cells involve in airway hyperresponsiveness by exhibiting a receptor that recognizes methacholine: muscarinic receptor-3 (M3).

The mast cells discharge serotonin when methacholine binds M3. Then, the serotonin acts on nerve cells, which in turn regulate the airways. Thus, the airways synthesize acetylcholine, which also has an effect on M3 in smooth muscle cells and induces the trachea to contract even more. A vicious cycle starts.

The discovery of the researchers also implies that drugs such as tiotropium, which were earlier considered to work mainly by blocking M3 in smooth muscle, are possibly also efficacious since they inhibit activation through M3 in mast cells. As a result, the mast cells’ potential to quickly release serotonin in response to different stimuli, which contributes to airway hyperresponsiveness, has been underestimated.