Study reveals new therapeutic targets for respiratory relaxation

Study reveals new therapeutic targets for respiratory relaxation

The narrowing of the bronchial tubes is what makes many lung diseases such as asthma so dangerous. Researchers have discovered a new signaling pathway that expands the airways.

Inhalation therapy for asthma and other obstructive lung diseases often loses its effect after long-term use. A research team led by Professor Daniela Wenzel from the Chair of Systems Physiology at the Ruhr University Bochum has now shown an alternative signaling pathway through which the body's own cannabinoids cause the bronchial tubes to expand. This gives hope for alternative treatment options. Asthma is also apparently associated with a deficiency of these cannabinoids in the bronchi, which could be one of the causes of the disease. The research team published their findings in the journal Nature Communications November 17, 2022.

Bronchi expanded by the body's own cannabinoids

Obstructive pulmonary disease is the third leading cause of death worldwide. These include chronic obstructive pulmonary disease (COPD), which affects many smokers, and bronchial asthma. During an asthma attack, the bronchi contract so much that it is no longer possible to breathe out - and this can be life-threatening.

Asthma is an inflammatory process, but the narrowing of the bronchi is fatal. That’s why we are very interested in regulating this bottleneck.”

Annika Simon, head of studies, Ruhr University Bochum

In an earlier study, the researchers also looked at the body's own cannabinoid system, specifically its effect in the blood vessels of the lungs. The best known endogenous cannabinoid is anandamide. “Since our results show that anandamide dilates the bronchi, we wanted to understand the exact mechanism behind it,” explains Daniela Wenzel.

Enzyme breaks down cannabinoid

It quickly became clear that the two best-known receptors for anandamide (CB1 and CB2) were irrelevant for this regulation. There must therefore be an alternative signaling pathway through which the messenger substance anandamide acts on the bronchi.

Daniela Wenzel and her team showed that this alternative pathway uses an enzyme called fatty acid amide hydrolase (FAAH). FAAH breaks down anandamide, which produces arachidonic acid, for example, which in turn is converted into prostaglandin E2. “We know that prostaglandin E2 can dilate the bronchi,” emphasizes Annika Simon. Prostaglandin E2 acts via certain receptors and leads to an increase in the messenger substance cAMP (cyclic adenosine monophosphate). “Established inhalation medications against asthma are aimed at precisely this increase in cAMP,” says Daniela Wenzel. So the goal is the same, but the path is different.

Anandamide deficiency in asthma

Wenzel and her team gradually decoded the signaling pathway. They found that the enzyme FAAH is localized both in the smooth muscle of the bronchi and in the ciliated epithelium. The cAMP increase after anandamide administration could be demonstrated both in mouse models and in human bronchial cells. To find out whether anandamide could also work in asthma patients, the team used a disease model in mice in which certain substances can be used to create artificial asthma. The administration of anandamide also caused the bronchi to dilate in these animals. “This means that asthma does not lead to resistance to anandamide,” explains Daniela Wenzel. In addition, the researchers found that asthmatic animals have less anandamide and other endocannabinoids in their bronchial system than healthy animals. “It is therefore possible that this anandamide deficiency is one of the causes of bronchial asthma,” concludes Daniela Wenzel.

The discovery of the new signaling pathway could also open up new opportunities to intervene in the disease process. “But there is still a long way to go and it will certainly take several years,” emphasizes Daniela Wenzel. She expressly warns patients not to experiment with cannabis plants. "We cannot draw any direct conclusions about plant cannabinoids from the findings on the body's own cannabinoids. Exactly which other ingredients are found in cannabis plants in addition to the known cannabinoids is completely unclear. In addition, the plants sometimes contain harmful substances." Nevertheless, the findings of this study already point towards a better understanding of the body's cannabinoid system, which could lead to new treatment options for lung diseases in a few years.

Source:

Ruhr University Bochum

Reference:

Simon, A., et al. (2022) The endocannabinoid anandamide is a respiratory depressant in health and illness. Nature communication. doi.org/10.1038/s41467-022-34327-0.

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