image: Green cells show markers of the lung epithelium, red cells are undergoing senescence. The nuclei are stained in blue. view more
Credit: Source: Helmholtz Zentrum München
Pulmonary fibrosis can possibly be attributed to a kind of cellular aging process, which is called senescence. This has been shown by researchers from the Helmholtz Zentrum München, partner in the German Center for Lung Research (DZL). As they report in the European Respiratory Journal, they have already successfully counteracted this mechanism in the cell culture with the help of drugs.
Pulmonary fibrosis causes the patient's lung tissue to scar, resulting in progressive pulmonary function deterioration. In particular, the surface of the alveoli (called the alveolar epithelium) is often affected. If the disease's origin is unknown, the condition is called idiopathic pulmonary fibrosis, or IPF for short. "The treatment options for IPF have been few and far between," explains Dr. Mareike Lehmann, scientisit in the Lung Repair and Regeneration Research Unit (LRR) at the Helmholtz Zentrum München. "We are therefore attempting to understand how the disease comes about so that we can facilitate targeted treatment."
In the current work, Lehmann and additional researchers, headed by department head Prof. Dr. Dr. Melanie Königshoff, have now succeeded in solving another piece of the puzzle. "In both the experimental model and in the lungs of IPF patients, we were able to show that some cells in the alveolar epithelium have markers for senescence*," explains study leader Königshoff. "Because the occurrence of IPF increases with age, this was already suspected. We have now succeeded in proving this hypothesis."
Senescence promotes pulmonary fibrosis in two ways
Senescence impairs lung function in two ways: It prevents lung cells from dividing when they need to be replaced. And senescent cells secrete mediators that further promote fibrosis. Since this effect also plays a role in cancer, the scientists were able to access an already existing group of medicines, the so-called senolytic drugs that selectively kill off senescent cells.
Pulmonary fibrosis stopped in the cell culture
In order to test possible treatment strategies, the scientists placed the affected cells into a three-dimensional cell culture and examined the drugs's effect ex vivo, so to speak. Mareike Lehmann: "We observed that this caused a decline in the quantity of secreted mediators and additionally a reduction in the mass of connective tissue proteins, which are greatly increased in the disease."
Altogether, the study shows that senescence in the cells of the alveolar epithelium can contribute to the development and worsening of IPF. This finding is new and constitutes a possible starting point for the development of new treatments.
Further information
* Cellular senescence describes a type of arrested growth during which the cells no longer divide. There are various causes of senescence: Damage to the DNA is just as possible as is the attainment of a maximum number of divisions (limited by the so-called telomeres). There are a number of markers that indicate senescence. In the current test, these were the molecules p16, p21 and a positive test for beta-galactosidase activity.
Background: Just recently, scientists at Helmholtz Zentrum München have shown that autoimmune reactions may be a causal factor of IPF.
Melanie Königshoff's research unit is a part of the German Center for Lung Research (DZL). Since the end of last year, she is also been setting up a new laboratory at the University of Colorado, Denver, where she will further expand her research program on lung regeneration. The co-authors Rita Costa, Wioletta Skronska-Wasek und Stephan Klee are members of the CPC Research School "Lung Biology and Disease" and participants in the Helmholtz Graduate School for Environmental Health (HELENA).
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Original-Publikation: Lehmann, M. et al. (2017): Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo. European Respiratory Journal, DOI: 10.1183/13993003.02367-2016
The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www.helmholtz-muenchen.de/en
The Lung Repair and Regeneration Research Unit is part of the Comprehensive Pneumology Center (CPC), which is a joint undertaking of the Helmholtz Zentrum München, Ludwig Maximilian University Munich with its University Hospital, and the Asklepios Specialist Clinics Munich-Gauting. The CPC's objective is to conduct research on chronic lung diseases in order to develop new diagnostic tools and therapies. The LRR Research Unit examines new mechanisms and repair processes in the lungs for a better understanding that will allow the development of new therapeutic approaches. The unit also focuses on developing new methods in order to reduce the gap between pre-clinical research and its application on patients. The CPC is a facility of the German Center for Lung Research (Deutsches Zentrum für Lungenforschung - DZL). http://www.helmholtz-muenchen.de/lrr
The German Center for Lung Research (DZL) pools German expertise in the field of pulmonology research and clinical pulmonology. The association's head office is in Giessen. The aim of the DZL is to find answers to open questions in research into lung diseases by adopting an innovative, integrated approach and thus to make a sizeable contribution to improving the prevention, diagnosis and individualized treatment of lung disease and to ensure optimum patient care. http://www.dzl.de/index.php/en
Contact for the media: Department of Communication, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg - Tel. +49 89 3187 2238 - Fax: +49 89 3187 3324 - E-mail: presse@helmholtz-muenchen.de
Scientific contact: Dr. Dr. Melanie Königshoff, Helmholtz Zentrum München - German Research Center for Environmental Health, Comprehensive Pneumology Center, Max-Lebsche-Platz 31, 81377 München, Germany - Tel. +49 89 3187 4668 - E-mail: melanie.koenigshoff@helmholtz-muenchen.de
Journal
European Respiratory Journal