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New hope regarding lung diseases

Lung research at Helmholtz Munich has made some spectacular breakthroughs. They could pave the way for the therapy of serious diseases.

Lung research at Helmholtz Munich has made some spectacular breakthroughs. They could pave the way for the therapy of serious diseases.

Lung model simulates pulmonary fibrosis

The high-tech device that Dr. Otmar Schmid and and his Postdoc Dr. Ali Doryab built is located behind closed doors in a medical laboratory of the Lung Health and Immunity Institute (LHI). Tubes are mounted to it, along with two larger vessels and a membrane that raises and lowers. "This is our bioreactor," Schmid says, "a kind of artificial lung." A device that can be used, for example, to study how effective newly developed drugs are when patients inhale them. This opens up completely new possibilities for lung research.

 

The highly complex device simulates pulmonary fibrosis - a disease in which the tissue hardens and becomes less elastic. As a result, the lungs lose volume for breathing. This is exactly what the model imitates - with a stretchable membrane on which lung cells grow, whose stretchability can be changed.

 

Video: BETA-Membrane of the mini-lung-fibrosis model (© Ali Doryab | Helmholtz Munich)
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Until now, studying lung fibrosis has been a problem for researchers because artificial models using lung cells were oversimplified. Comparisons with animals are also often out of the question because there are too many differences from humans in this case. The bioreactor of the Munich researchers fills this gap, even if Otmar Schmid qualifies: "A human lung consists of about 60 different cell types. We simulate three in our model - so it's much less complex."

The three cell types, however, are precisely those that occur at the air barrier and the blood barrier; the place in the lung where oxygen enters the bloodstream. For the study of pulmonary fibrosis, this is the crucial spot. "For our specific questions, the model offers exactly the right possibilities," says Otmar Schmid. In pneumology, the field of lung medicine, the lung model caused a sensation with its innovative approach - along with other spectacular developments from Helmholtz Munich.

 

 

Deciphering diseases with the latest technology

Modern high-tech methods are promising when it comes to finding drugs for lung diseases. One example is the so-called single-cell analyses, which can be used to seamlessly track developments in individual cells. "In the past, we could look at the lungs when a human or animal had died. That's when we saw the endpoint of a disease. But we were unable to observe how it developed over time," says Otmar Schmid. "With the new methods, we can now determine interaction pathways and find out in real time what exactly a certain treatment does, for example."

Schmid has high hopes for drugs that are inhaled - drugs for lung diseases, but also for completely different diseases. "So far, the problem is that patient behavior has a big impact on how much of the active ingredient actually gets there," Schmid says. Correct inhalation requires some practice, while a pill, for example, automatically delivers the same amount of an active ingredient to the target each time.

Schmid is therefore working with his team on what he calls "precision inhalation therapy": "You can imagine it as being as simple and correct for sufferers to inhale as if they were taking a pill. They hold a device in front of their mouth and continue breathing normally - and at some point they get the message that they've absorbed enough of the active ingredient." In this field, Otmar Schmid believes, great strides in development are ahead.

 

On the trail of COPD

Behind all these developments is the research team of Prof. Ali Önder Yildirim, head of the Institute for Lung Health and Immunity (LHI) at Helmholtz Munich. "The lungs have always fascinated me," Yildirim says: "Without nutrition, a person can last three weeks, without water, three days - but without air, three minutes at most." Despite this, research into lung diseases led a somewhat shadowy existence worldwide for many decades. This is despite the fact that the lungs are behind one of the world's leading causes of death - chronic obstructive pulmonary disease (COPD), in which lung tissue is gradually destroyed.

New therapeutic approaches

In two spectacular studies, Yildirim and his team have made important advances in the fight against COPD: they have been able to stop the progression of the disease in experiments on mice and organoids, and even ensure that a damaged lung regenerates."At the molecular level, the way the disease works is that B cells accumulate and destroy the alveoli," Ali Önder Yildirim explains. "So we wondered if we could stop COPD by preventing the accumulation of B cells."

B cells clump together to form what is known as lymphoid follicles. So the goal is to destroy those follicles. To do this, Yildirim and his team used clotrimazole - an active ingredient commonly used to treat fungal infections. They found that it was indeed possible to halt the progression of the disease in mouse experiments.

 

How the lungs can repair themselves

The core: Certain molecules cause cell death in the lung - and at the same time prevent the lung from regenerating itself. These so-called ligands are formed in T and B cells of the lung. They then dock onto receptors of epithelial cells; it is from this site that they do the damage. "Our idea was therefore to block these ligands," explains Ali Önder Yildirim. With his team, he first tried out this idea on mice whose lungs had been damaged by exposure to smoke.
"And one day, a coworker came to my office and said, "I think we have something special!" recalls Yildirim. He immediately ran off to the lab to see for himself: the sick animals, he noticed, looked healthy again. He immediately had the amazing experiment repeated - and was successful again. "The fact that this was possible and that the disease that had already developed could be reversed, is unique in the world." In the meantime, the researchers have been able to achieve this success not only in mice, but also in so-called organoids - artificial organs that resemble those of humans.

The powers to regenerate are apparently innate in the lungs. "The lungs have an incredible amount of contact with the outside world. It is one of the organs with the largest surface area," says Ali Önder Yildirim. With every breath, the body absorbs all the substances that are in the air via the lungs. Coping with negative influences is therefore also important for the lungs: "But because they are often permanently exposed to pollutants, their ability to regenerate is limited."

Because of many air pollutants, COPD is also so common. Originally, chronic obstructive pulmonary disease was considered a smoker's disease. Today, it is known that it is not only triggered by cigarette smoke, but also by pollutants in the air, for example. Ali Önder Yildirim has his goal clearly in mind: currently, COPD is the third most common cause of death worldwide - "my vision is to fight the disease so well that it only ranks 20th!"

The researchers at Helmholtz Munich are contributing to this progress with their know-how. The innovations will help with lung diseases such as COPD or pulmonary fibrosis, but also with other diseases.

Current Clinical Studies

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