How the body's own cannabinoids far-range the bronchi

The research team led by Prof. Dr. Daniela Wenzel, Dr. Michaela Matthey, Alexander Seidinger and Annika Simon (from left) want to know how the bronchi can be set far.
Photo Credit: RUB, Marquard

Narrowing the bronchi makes many lung diseases like asthma so dangerous. Researchers have discovered a new signaling pathway that leads to the expansion of the respiratory tract.

Inhalation drugs against asthma and other obstructive pulmonary diseases often decrease in their effects after prolonged use. A research team led by Prof. Dr. Daniela Wenzel from the Department of Systems Physiology at the Ruhr University Bochum was now able to show an alternative signal path through which the body's own cannabinoids lead to the bronchi being expanded. This raises hopes for alternative treatment options. Asthma also appears to be associated with a lack of these cannabinoids in the bronchi, which could be one of the causes of the disease. The research team reports in the journal Nature Communications.

The bronchi are far from the body's own cannabinoids

Obstructive lung diseases are the third leading cause of death worldwide. These include, for example, the chronic obstructive pulmonary disease COPD, from which many smokers suffer, but also bronchial asthma. In an asthma attack, the bronchi contracts so strongly that exhalation is no longer possible - this can be life-threatening. "Asthma is an inflammatory process, but the narrowing of the bronchi is fatal," explains Annika Simon, first author of the study. “That is why we are particularly interested in regulating this narrowing."

In a previous work, the body's own cannabinoid system was already in focus, but at that time its effect in the blood vessels of the lungs. The best-known body cannabinoid is anandamide. "Since our results show that anandamide expands the bronchi, we wanted to clarify the exact mechanism behind it," explains Daniela Wenzel.

Enzyme breaks down cannabinoid

The force measurements in the bronchi above. After administration of anandamide, the tension subsides. Below left is a histological section of a mouse lung with a central bronchus and below right human bronchial muscle cells with red immune coloring against FAAH, the cell nuclei are colored blue.
 Credit: Annika Simon

It quickly became apparent that the two best-known receptors for anandamide (CB1 and CB2) play no role in this regulation. So, there must be an alternative signaling pathway through which the messenger anandamide acts on the bronchi.

Daniela Wenzel and her team were able to show that this alternative route leads through an enzyme, the so-called fatty acid amide hydrolase, FAAH for short, from the English word fatty acid amide hydrolase. FAAH breaks down anandamide, which, among other things, produces arachidonic acid, which in turn is converted into prostaglandin E2. "Prostaglandin E2 is known to be able to expand the bronchi," explains Annika Simon. Prostaglandin E2 works via certain receptors and leads to an increase in the messenger substance cAMP (cyclic adenosine monophosphate). "Exactly, the increase in the cAMP is also aimed at proven inhalation drugs against asthma," says Daniela Wenzel. So the goal is the same, but the way is different.

Anandamide deficiency in asthma

Wenzel and her team gradually turned down the signal path. They were able to show that the FAAH enzyme is both in the smooth muscles of the bronchi and in the flicker epithelium. The increase in cAMP after anandamide administration was demonstrated both in the mouse model and on human bronchial cells. In order to find out whether anandamide could also work for asthma sufferers, the team used a disease model in mice, in which an artificial asthma can be generated by certain substances. The administration of anandamide also led to the bronchi being widened in these animals. "So, asthma does not lead to resistance to anandamide," concludes Daniela Wenzel. In addition, the researchers were able to demonstrate that asthmatic animals have less anandamide and other endocannabinoids in their bronchial system than healthy ones. "So, this anandamide deficiency could be one of the causes of bronchial asthma disease," concludes Daniela Wenzel.

The discovery of the new signaling pathway could also open up new opportunities to intervene in the disease. "So far, however, it is still a long way that will surely take several years," emphasizes Daniela Wenzel. She expressly warns those affected against trying cannabis plants. “You cannot draw any direct conclusions from the knowledge of the body's own cannabinoids on the plant cannabinoids. It is completely unclear which other ingredients are found in cannabis plants in addition to the well-known cannabinoids. The plants sometimes contain harmful substances”. The findings of this study are nevertheless trend-setting for a better understanding of the body's own cannabinoid system, which could lead to new therapeutic options for lung diseases in a few years.

Promotion
The work was funded by the German Research Foundation (funding code: WE4461 / 1-1).

Source/Credit: Ruhr University Bochum

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