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Research at CPC-M - COPD – soon a common disease?

Research at CPC-M

COPD – soon a common disease?

Stop severe course of COPD – with an antifungal agent?

What is COPD?

COPD (chronic obstructive pulmonary disease) is estimated to be the third leading cause of death worldwide. It occurs when people are exposed to harmful environmental gases or particles for a long time, e.g. by pollutants in the air, but usually by cigarette smoke. Colloquially, this lung disease is therefore called smoker's lung. COPD symptoms include chronic bronchitis, coughing and shortness of breath. The disease is usually accompanied by pulmonary emphysema, in which the alveoli are destroyed and overstretched. This causes the patient to experience shortness of breath. COPD cannot be cured, it is only possible to alleviate the symptoms or slow the progression of the disease. Depending on the severity and impairment of lung function, the disease is divided into the following stages: GOLD 1 (mild), GOLD 2 (moderate), GOLD 3 (severe), GOLD 4 (very severe).
 

Graphical representation of alveoli with COPD - © Angelika Kramer Grafikdesign
Graphical representation of alveoli with COPD

After COPD diagnosis – why does the disease take such a severe course?

In COPD patients in the more severe GOLD stages 3 and 4, we observe an increased incidence of B cells (lymphocytes). The B cells are present in a special structure, as lymphoid follicles. Above all, they are responsible for the extremely poor course of COPD because they promote the formation of pulmonary emphysema. These lymphoid follicles need to be destroyed in order to prevent further progression of the disease.

What could stop the formation of pulmonary emphysema?

What we found out: The key element in the formation of lymph follicles from B cells in the epithelial cells of the respiratory tract is the cholesterol metabolism of the cells. In mouse experiments, it was shown that mice whose cholesterol metabolism is genetically completely blocked do not form lymph follicles. So the next question was: How do we develop a therapeutic agent that has exactly this function – blocking the cholesterol metabolism?

iBALT Lymphfollikel

Lung tissue with lymph follicle - © Helmholtz-Zentrum München

We discovered clotrimazole, a compound known from the treatment of fungal infections, whose patent related to this mechanism of action has expired. Again in mouse experiments, we saw that it is precisely this drug that inhibits the cholesterol metabolism in epithelial cells. No lymph follicles are formed, a progression of the disease, e.g. from stage 2 to 3 or 4, could be prevented.

Further questions and research approaches for improved COPD therapy:

Which agent in the azole group acts as the best inhibitor, which is the most effective in blocking cholesterol metabolism? This is what we will examine in the next step.

We also want to find the best way to deliver the drug to its target site: the epithelial cells of the lungs. With the non-animal ALICE-Cloud test system we are  investigating different routes of inhalation therapies. This cell system, developed at the CPC-M by Dr. Otmar Schmid and his team, imitates the air-fluid conditions in lung tissue. ALICE-CLOUD makes it possible to test agents for inhalation therapies under realistic physiological conditions in the laboratory – but not on living organisms.

Last but not least, we have a great hope: that the therapeutic agent, the drug can be used as a "key effect" in other lung diseases – because the damaging structure of lymphoid follicles also plays a role in other lung diseases such as lung cancer or pulmonary fibrosis.
 

Head of Group

Dr. Ali Önder Yildirim
oender.yildirim(at)helmholtz-muenchen.de

+49 89 3187 - 4037

Helmholtz Zentrum München
Institute of Lung Biology and Disease
Ingolstädter Landstr. 1

85764 Neuherberg

Team

Dr. Ali Önder Yildirim, Head
Christine Hollauer, Technical Assistant
Carolina Ballester-Lopez, Doctoral Student (PhD)
Gizem Günes, Doctoral Student (PhD)
Sarah Schulte-Döinghaus, Master Student
Carmela Morrone, Doctoral Student (PhD)
Maximilian Pankla, Technical Assistant
Dr. Thomas Conlon, Postdoctoral Fellow
Dr. Heng Shou Liu, Postdoctoral Fellow
Dr. Barkha Srivastava, Postdoctoral Fellow
Verena Haefner, Doctoral Student (PhD)

Publications:

Jia J et al., EMBO Mol Med., 2018:

Cholesterol metabolism promotes B-cell positioning during immune pathogenesis of chronic obstructive pulmonary disease

Blog article about the project in newsletter of german ministry of education and research,  september 2018 (german only):

COPD – tödliche Entzündung der Lunge verhindern

 

 

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