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Helmholtz Munich

Lehmann Lab

Lung Inflammaging

The Lehmann Lab aims to understand how aging predisposes the lung to the development of chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).

The Lehmann Lab aims to understand how aging predisposes the lung to the development of chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD).

Cellular senescence in chronic lung diseases

We aim to understand how cellular aging affects stem cell capacities and cell-cell crosstalk, especially between immune cells and stem cells. In order to allow the aging lung to efficiently repair, we aim to develop biomarkers as well as therapeutic strategies targeting cellular aging phenotypes, thereby opening novel avenues for the diagnosis and treatment of chronic lung diseases.

Lung Aging in a dish

To be able to test potential anti-senescent therapies in the human system, we are developing a human aging model based on human precision cut lung slices (PCLS) that displays relevant hallmarks of aging such as cellular senescence. This model will be used to verify target engagement of anti-senescent therapies in the human system and will help to screen for relevant biomarkers for companion diagnostics development.

Scientists at Lehmann Lab

Nora Bramey

MD Student

Camila Melo Narvaez

Doctoral Student (PhD)

Amina Orlovic

Student Assistant

Fenja See

Doctoral Student (MD)

Carina Steinchen

MD student

Publications

2022, Review in American Journal of Physiology - Lung Cellular and Molecular Physiology

Stem cells, cell therapies, and bioengineering in lung biology and disease 2021.

The 9th biennial conference titled "Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases" was hosted virtually, due to the ongoing COVID-19 pandemic, in collaboration with the University of Vermont Larner College of Medicine, the National Heart, Lung, and Blood Institute, the Alpha-1 Foundation, the Cystic Fibrosis Foundation, and the International Society for Cell & Gene Therapy. The event was held from July 12th through 15th, 2021 with a pre-conference workshop held July 9th. As in previous years the objectives remained to review and discuss the status of active research areas involving stem cells, cellular therapeutics, and bioengineering as they relate to the human lung. Topics included: 1) technological advancements in the in situ analysis of lung tissues, 2) new insights into stem cell signalling and plasticity in lung remodelling and regeneration, 3) the impact of extracellular matrix in stem cell regulation and airway engineering in lung regeneration, 4) differentiating and delivering stem cell therapeutics to the lung, 5) regeneration in response to viral infection, and 6) ethical development of cell-based treatments for lung diseases. This selection of topics represents some of the most dynamic and current research areas in lung biology. The virtual workshop included active discussion on state-of-the-art methods relating to the core features of the 2021 conference, including in-situ protemics, lung-on-chip, iPSC-airway differentiation, and light sheet microscopy. The conference concluded with an open discussion to suggest funding priorities and recommendations for future research directions in basic and translational lung biology.

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Handbook of Experimental Pharmacology

WNT signalling in lung physiology and pathology.

The main physiological function of the lung is gas exchange, mediated at the interface between the alveoli and the pulmonary microcapillary network and facilitated by conducting airway structures that regulate the transport of these gases from and to the alveoli. Exposure to microbial and environmental factors such as allergens, viruses, air pollution, and smoke contributes to the development of chronic lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and lung cancer. Respiratory diseases as a cluster are the commonest cause of chronic disease and of hospitalization in children and are among the three most common causes of morbidity and mortality in the adult population worldwide. Many of these chronic respiratory diseases are associated with inflammation and structural remodelling of the airways and/or alveolar tissues. They can often only be treated symptomatically with no disease-modifying therapies that normalize the pathological tissue destruction driven by inflammation and remodelling. In search for novel therapeutic strategies for these diseases, several lines of evidence revealed the WNT pathway as an emerging target for regenerative strategies in the lung. WNT proteins, their receptors, and signalling effectors have central regulatory roles under (patho)physiological conditions underpinning lung function and (chronic) lung diseases and we summarize these roles and discuss how pharmacological targeting of the WNT pathway may be utilized for the treatment of chronic lung diseases.

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2021, Scientific Article in British Journal of Pharmacology

A drug screen with approved compounds identifies amlexanox as a novel Wnt/β-catenin activator inducing lung epithelial organoid formation.

Background and purpose: Emphysema is an incurable disease characterized by loss of lung tissue leading to impaired gas exchange. Wnt/β-catenin signaling is reduced in emphysema and exogenous activation of the pathway in experimental models in vivo and in human ex vivo lung tissue improves lung function and structure. We sought to identify a pharmaceutical able to activate Wnt/β-catenin signaling and asses its potential to activate lung epithelial cells and repair. Experimental approach: We screened 1216 human-approved compounds for Wnt/β-catenin signaling activation using luciferase reporter cells, and selected candidates based on their computational predicted protein targets. We further performed confirmatory luciferase reporter and metabolic activity assays. Finally, we studied the regenerative potential in murine adult epithelial cell derived lung organoids and in vivo using a murine elastase-induced emphysema model. Key results: The primary screen identified 16 compounds that significantly induced Wnt/β-catenin-dependent luciferase activity. Selected compounds activated Wnt/β-catenin signaling without inducing cell toxicity or proliferation. Two compounds were able to promote organoid formation, which was reversed by pharmacological Wnt/β-catenin inhibition, confirming the Wnt β-catenin-dependent mechanism of action. Amlexanox was used for in vivo evaluation and preventive treatment resulted in improved lung function and structure in emphysematous mouse lungs. Moreover, gene expression of Hgf, an important alveolar repair marker, was increased, whereas disease marker Eln was decreased, indicating that amlexanox induces pro-regenerative signaling in emphysema. Conclusion and implications: Using a drug screen based on Wnt/β-catenin activity, organoid assays, and a murine emphysema model, amlexanox was identified as a novel potential therapeutic for emphysema.

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Contact

Dr. Mareike Lehmann

Team Leader