Skip to main content
Helmholtz Munich | LHI
01:0

Environmental Health Center Lung Health and Immunity

We explore the immunological mechanisms underlying chronic lung diseases such as COPD, lung fibrosis, asthma, lung cancer and the complications following lung transplantation to translate them into preventative and therapeutic approaches for patients.

We explore the immunological mechanisms underlying chronic lung diseases such as COPD, lung fibrosis, asthma, lung cancer and the complications following lung transplantation to translate them into preventative and therapeutic approaches for patients.

Our Research Areas

Helmholtz Munich
Lead: Isis Fernandez

Immunometabolic Reprogramming

We strive towards pioneering experimental and human models of immunometabolic reprogramming in the lungs and translating our findings into meaningful diagnostic and therapeutic tools. The investigation of structural-immune and immune-immune cell interaction, reprogramming and the pulmonary epimmunome facilitates a better understanding of the pathogenesis of chronic pulmonary diseases. It will lead us to immune-driven target identification and prioritization to broaden the therapeutic landscape in chronic lung diseases.

Helmholtz Munich
Lead: Herbert Schiller

Cell Circuits in Systems Medicine of Lung Disease

The main aim of this research program is to understand how cells are wired together into circuits and thereby influence each other in lung health and disease. We study patient and mouse tissues and organotypic ex vivo models at single cell resolution. This enables us to reconstruct regulatory cellular circuits and identify fundamental cellular and molecular mechanisms of lung disease and regeneration, as well as associated clinically relevant biomarkers in an era of precision medicine.

Helmholtz Munich
Lead: Tobias Stöger

Environmental Barrier Immunity

We aim to understand the cellular pathways maintaining the functionality of the respiratory barrier and how tissue homeostasis gets affected by specific environmental, airborne challenges. So far, focus has been on acute or chronic exposure scenarios of cigarette smoke and combustion derived or engineered nanoparticles and their contribution to the development of chronic lung diseases such as COPD, asthma, and pulmonary fibrosis.

News

Director

Dr. Ali Önder Yildirim

Director & Team Leader

Deputy Director

Dr. Herbert Schiller

Deputy Director & Team Leader

Management

Franziska Hauptkorn

Head of Operations Management

Contact

Kaori Sumikawa

Executive Assistant

Our Labs

Helmholtz Munich
Burgstaller Lab

Immunotherapeutic Technologies

View lab
Helmholtz Munich
Fernandez Lab

Immune networks in chronic lung diseases

View lab
Tobilander - stock.adobe.com
Hilgendorff Lab

Mechanism of Neonatal Chronic Lung Disease

View lab
Anusorn - stock.adobe.com
Kapellos Lab

Immunoregulation in obstructive respiratory diseases

View Lab
Helmholtz Munich
tonaquatic - stock.adobe.com
Schiller Lab

Cell Circuits in Lung Disease

View Lab
7activestudio - stock.adobe.com
Schmid Lab

Pulmonary Aerosol Delivery

View Lab
Helmholtz Munich
Staab-Weijnitz Lab

Collagen biosynthesis and maturation in lung fibrosis

View Lab
Helmholtz Munich | Doris Hammerschmidt
Stöger Lab

Dynamics of Pulmonary Inflammation

View Lab
Helmholtz Munich | Angelika Kramer Grafik Design
Conlon/Yildirim Lab

Immunopathology of COPD

View Lab
Helmholtz Munich | Doris Hammerschmidt
koldunova_anna - stock.adobe.com

Scientists at LHI

Dr. Isis E. Fernandez

Team Leader

PD Dr. med. Anne Hilgendorff

Team Leader

Dr. Herbert Schiller

Deputy Director & Team Leader

Dr. Otmar Schmid

Team Leader

Clinical Trials

Helmholtz Munich | Angelika Kramer Grafik Design
Ongoing trial

CatBOS

Cathepsin-B (CatB) as a new biomarker and therapeutic target for early bronchiolotis obliterans syndrome (BOS) after lung transplantation

View clinical trial
Helmholtz Munich | Angelika Kramer Grafik Design
Enrolling in 2022

LeT-COPD

The study will investigate the role of lymphotoxin-expressing T cells in the development of tissue damage in COPD pathogenesis. The goal is to develop a predictive model that identifies subtypes at risk for developing severe COPD at early stages of COPD. This should enable more effective, personalized interventions.

Publications

2022, Scientific Article in Biochimica et Biophysica Acta - Molecular Basis of Disease

Proteomics reveals antiviral host response and NETosis during acute COVID-19 in high-risk patients.

SARS-CoV-2 remains an acute threat to human health, endangering hospital capacities worldwide. Previous studies have aimed at informing pathophysiologic understanding and identification of disease indicators for risk assessment, monitoring, and therapeutic guidance. While findings start to emerge in the general population, observations in high-risk patients with complex pre-existing conditions are limited. We addressed the gap of existing knowledge with regard to a differentiated understanding of disease dynamics in SARS-CoV-2 infection while specifically considering disease stage and severity. We biomedically characterized quantitative proteomics in a hospitalized cohort of COVID-19 patients with mild to severe symptoms suffering from different (co)-morbidities in comparison to both healthy individuals and patients with non-COVID related inflammation. Deep clinical phenotyping enabled the identification of individual disease trajectories in COVID-19 patients. By the use of the individualized disease phase assignment, proteome analysis revealed a severity dependent general type-2-centered host response side-by-side with a disease specific antiviral immune reaction in early disease. The identification of phenomena such as neutrophil extracellular trap (NET) formation and a pro-coagulatory response characterizing severe disease was successfully validated in a second cohort. Together with the regulation of proteins related to SARS-CoV-2-specific symptoms identified by proteome screening, we not only confirmed results from previous studies but provide novel information for biomarker and therapy development.

Read more
2022, Scientific Article in American Journal of Physiology - Regulatory, Integrative and Comparative Physiology

Aqp5--/-- mice exhibit reduced maximal O2 consumption under cold exposure, normal pulmonary gas exchange, and impaired formation of brown adipose tissue.

The fundamental body functions that determine maximal O2 uptake (VO2,max) have not been studied in Aqp5 --/-- (aquaporin 5, AQP5) mice. We measured VO2,max to globally assess these functions and then investigated why it was found altered in Aqp5 --/-- mice. VO2,max was measured by the Helox technique, which elicits maximal metabolic rate by intense cold exposure of the animals. We found VO2,max reduced in Aqp5 --/-- mice by 20 - 30% compared to WT. Since AQP5 has been implicated to act as a membrane channel for respiratory gases, we studied whether this is due to the known lack of AQP5 in the alveolar epithelial membranes of Aqp5 --/-- mice. Lung function parameters as well as arterial O2 saturation were normal and identical between Aqp5 --/-- and WT mice, indicating that AQP5 does not contribute to pulmonary O2 exchange. The cause for the decreased VO2,max thus might be found in decreased O2 consumption of an intensely O2-consuming peripheral organ such as activated BAT. We found indeed that absence of AQP5 greatly reduces the amount of interscapular BAT formed in response to 4 weeks' cold exposure, from 63% in WT to 25% in Aqp5 --/-- animals. We conclude that lack of AQP5 does not affect pulmonary O2 exchange, but greatly inhibits transformation of white to brown adipose tissue. Since under cold exposure BAT is a major source of the animals' heat production, reduction of BAT likely causes the decrease in VO2,max under this condition.

Read more
2022, Scientific Article in Scientific Reports

Reference genes for the developing mouse lung under consideration of biological, technical and experimental confounders.

For gene expression analysis, the raw data obtained from RT-qPCR are preferably normalized to reference genes, which should be constantly expressed regardless of experimental conditions. Selection of reference genes is particularly challenging for the developing lung because of the complex transcriptional and epigenetic regulation of genes during organ maturation and injury repair. To date, there are only limited experimental data addressing reliable reference genes for this biological circumstance. In this study, we evaluated reference genes for the lung in neonatal C57BL/6 mice under consideration of biological, technical and experimental conditions. For that, we thoroughly selected candidates from commonly used reference genes side-by-side with novel ones by analyzing publicly available microarray datasets. We performed RT-qPCR of the selected candidate genes and analyzed their expression variability using GeNorm and Normfinder. Cell-specific expression of the candidate genes was analyzed using our own single-cell RNA-sequencing data from the developing mouse lung. Depending on the investigated conditions, i.e., developmental stages, sex, RNA quality, experimental condition (hyperoxia) and cell types, distinct candidate genes demonstrated stable expression confirming their eligibility as reliable reference genes. Our results provide valuable information for the selection of proper reference genes in studies investigating the neonatal mouse lung.

Read more
2022, Scientific Article in European Journal of Pharmaceutical Sciences

Towards a gold standard functional readout to characterize In Vitro lung barriers.

The development of biomimetic in vitro lung models as an alternative to animal studies is urgent to improve the predictability of the pharmacokinetics of potential new drugs. For pharmacokinetics studies, advanced in vitro lung models such as lung-chips should mimic a functional air-blood barrier. Unlike in vivo conditions, stem/primary cells and cell lines do not necessarily form a functional and tight barrier when cultured in vitro. Here, we explore the two gold standard techniques for monitoring barrier integrity: transepithelial electrical resistance (TEER) and permeability. We discuss the advantages and limitations of these methods, provide recommendations for methodological improvements, and we elude on possible future directions.

Read more
2022, Scientific Article in Frontiers in Cellular and Infection Microbiology

Effects of immunophilin inhibitors and non-immunosuppressive analogs on coronavirus replication in human infection models.

Rationale: Human coronaviruses (HCoVs) seriously affect human health by causing respiratory diseases ranging from common colds to severe acute respiratory diseases. Immunophilins, including peptidyl-prolyl isomerases of the FK506-binding protein (FKBP) and the cyclophilin family, are promising targets for pharmaceutical inhibition of coronavirus replication, but cell-type specific effects have not been elucidated. FKBPs and cyclophilins bind the immunosuppressive drugs FK506 and cyclosporine A (CsA), respectively. Methods: Primary human bronchial epithelial cells (phBECs) were treated with CsA, Alisporivir (ALV), FK506, and FK506-derived non-immunosuppressive analogs and infected with HCoV-229E. RNA and protein were assessed by RT-qPCR and immunoblot analysis. Treatment with the same compounds was performed in hepatoma cells (Huh-7.5) infected with HCoV-229E expressing Renilla luciferase (HCoV-229E-RLuc) and the kidney cell line HEK293 transfected with a SARS-CoV-1 replicon expressing Renilla luciferase (SARS-CoV-1-RLuc), followed by quantification of luminescence as a measure of viral replication. Results: Both CsA and ALV robustly inhibited viral replication in all models; both compounds decreased HCoV-229E RNA in phBECs and reduced luminescence in HCoV-229E-RLuc-infected Huh7.5 and SARS-CoV-1-RLuc replicon-transfected HEK293. In contrast, FK506 showed inconsistent and less pronounced effects in phBECs while strongly affecting coronavirus replication in Huh-7.5 and HEK293. Two non-immunosuppressive FK506 analogs had no antiviral effect in any infection model. Conclusion: The immunophilin inhibitors CsA and ALV display robust anti-coronaviral properties in multiple infection models, including phBECs, reflecting a primary site of HCoV infection. In contrast, FK506 displayed cell-type specific effects, strongly affecting CoV replication in Huh7.5 and HEK293, but inconsistently and less pronounced in phBECs.

Read more
2022, Review in Frontiers in Immunology

The role of tumor-associated macrophages and soluble mediators in pulmonary metastatic melanoma.

Skin malignant melanoma is a highly aggressive skin tumor, which is also a major cause of skin cancer-related mortality. It can spread from a relatively small primary tumor and metastasize to multiple locations, including lymph nodes, lungs, liver, bone, and brain. What’s more metastatic melanoma is the main cause of its high mortality. Among all organs, the lung is one of the most common distant metastatic sites of melanoma, and the mortality rate of melanoma lung metastasis is also very high. Elucidating the mechanisms involved in the pulmonary metastasis of cutaneous melanoma will not only help to provide possible explanations for its etiology and progression but may also help to provide potential new therapeutic targets for its treatment. Increasing evidence suggests that tumor-associated macrophages (TAMs) play an important regulatory role in the migration and metastasis of various malignant tumors. Tumor-targeted therapy, targeting tumor-associated macrophages is thus attracting attention, particularly for advanced tumors and metastatic tumors. However, the relevant role of tumor-associated macrophages in cutaneous melanoma lung metastasis is still unclear. This review will present an overview of the origin, classification, polarization, recruitment, regulation and targeting treatment of tumor-associated macrophages, as well as the soluble mediators involved in these processes and a summary of their possible role in lung metastasis from cutaneous malignant melanoma. This review particularly aims to provide insight into mechanisms and potential therapeutic targets to readers, interested in pulmonary metastasis melanoma.

Read more
2022, Scientific Article in Patient preference and adherence

Basic determinants of disease knowledge in COPD patients: Results from COSYCONET.

Introduction: In many chronic diseases, including COPD, the patients' basic knowledge of the disorder has been shown to be relevant for the course of the disease. We studied which clinical and functional characteristics were related to this knowledge as well as the patients' satisfaction with their knowledge about COPD. Methods: The study population comprised 645 patients of GOLD grades 1-4 who participated in Visit 6 of the COSYCONET cohort (COPD and Systemic Consequences - Comorbidities Network). The assessments covered a broad panel of clinical and functional characteristics, including generic and disease-specific quality of life and the COPD Assessment Test (CAT). The study aim was addressed by two questions, referring to patients' knowledge of the meaning of FEV1 and the overall satisfaction with their knowledge of COPD. Results: Knowledge of FEV1 was higher in patients of higher spirometric GOLD grades or exacerbation risk, in males, with higher educational level, and after participation in a prior educational training on COPD. Patients with more detailed knowledge showed a higher satisfaction with their knowledge. Satisfaction was associated with higher generic quality of life and a lower CAT score. Furthermore, satisfaction was higher in patients with a treatment plan but lower in patients with cardiac comorbidities. It appeared that females with basic education, high burden from COPD and low quality of life had the greatest knowledge deficits. Discussion: The results suggest room for education programs adapted to the educational level of the participants. They also emphasize the major role of a disease management plan for the patients.

Read more
2022, Scientific Article in Biomedicines

Bioactive cell-derived ECM scaffold forms a unique cellular microenvironment for lung tissue engineering.

Chronic lung diseases are one of the leading causes of death worldwide. Lung transplantation is currently the only causal therapeutic for lung diseases, which is restricted to end-stage disease and limited by low access to donor lungs. Lung tissue engineering (LTE) is a promising approach to regenerating a replacement for at least a part of the damaged lung tissue. Currently, lung regeneration is limited to a simplified local level (e.g., alveolar-capillary barrier) due to the sophisticated and complex structure and physiology of the lung. Here, we introduce an extracellular matrix (ECM)-integrated scaffold using a cellularization-decellularization-recellularization technique. This ECM-integrated scaffold was developed on our artificial co-polymeric BETA (biphasic elastic thin for air-liquid interface cell culture conditions) scaffold, which were initially populated with human lung fibroblasts (IMR90 cell line), as the main generator of ECM proteins. Due to the interconnected porous structure of the thin (<5 µm) BETA scaffold, the cells can grow on and infiltrate into the scaffold and deposit their own ECM. After a mild decellularization procedure, the ECM proteins remained on the scaffold, which now closely mimicked the cellular microenvironment of pulmonary cells more realistically than the plain artificial scaffolds. We assessed several decellularization methods and found that 20 mM NH4OH and 0.1% Triton X100 with subsequent DNase treatment completely removed the fibroblasts (from the first cellularization) and maintains collagen I and IV as the key ECM proteins on the scaffold. We also showed the repopulation of the primary fibroblast from human (without chronic lung disease (non-CLD) donors) and human bronchial epithelial (16HBE14o-) cells on the ECM-integrated BETA scaffold. With this technique, we developed a biomimetic scaffold that can mimic both the physico-mechanical properties and the native microenvironment of the lung ECM. The results indicate the potential of the presented bioactive scaffold for LTE application.

Read more
2022, Review in NanoImpact

Analytical and toxicological aspects of nanomaterials in different product groups: Challenges and opportunities.

The widespread integration of engineered nanomaterials into consumer and industrial products creates new challenges and requires innovative approaches in terms of design, testing, reliability, and safety of nanotechnology. The aim of this review article is to give an overview of different product groups in which nanomaterials are present and outline their safety aspects for consumers. Here, release of nanomaterials and related analytical challenges and solutions as well as toxicological considerations, such as dose-metrics, are discussed. Additionally, the utilization of engineered nanomaterials as pharmaceuticals or nutraceuticals to deliver and release cargo molecules is covered. Furthermore, critical pathways for human exposure to nanomaterials, namely inhalation and ingestion, are discussed in the context of risk assessment. Analysis of NMs in food, innovative medicine or food contact materials is discussed. Specific focus is on the presence and release of nanomaterials, including whether nanomaterials can migrate from polymer nanocomposites used in food contact materials. With regard to the toxicology and toxicokinetics of nanomaterials, aspects of dose metrics of inhalation toxicity as well as ingestion toxicology and comparison between in vitro and in vivo conclusions are considered. The definition of dose descriptors to be applied in toxicological testing is emphasized. In relation to potential exposure from different products, opportunities arising from the use of advanced analytical techniques in more unique scenarios such as release of nanomaterials from medical devices such as orthopedic implants are addressed. Alongside higher product performance and complexity, further challenges regarding material characterization and safety, as well as acceptance by the general public are expected.

Read more
2022, Scientific Article in Nutrients

Improved Macro- and micronutrient supply for favorable growth and metabolomic profile with standardized parenteral nutrition solutions for very preterm infants.

Very preterm infants are at high risk for suboptimal nutrition in the first weeks of life leading to insufficient weight gain and complications arising from metabolic imbalances such as insufficient bone mineral accretion. We investigated the use of a novel set of standardized parenteral nutrition (PN; MUC PREPARE) solutions regarding improving nutritional intake, accelerating termination of parenteral feeding, and positively affecting growth in comparison to individually prescribed and compounded PN solutions. We studied the effect of MUC PREPARE on macro- and micronutrient intake, metabolism, and growth in 58 very preterm infants and compared results to a historic reference group of 58 very preterm infants matched for clinical characteristics. Infants receiving MUC PREPARE demonstrated improved macro- and micronutrient intake resulting in balanced electrolyte levels and stable metabolomic profiles. Subsequently, improved energy supply was associated with up to 1.5 weeks earlier termination of parenteral feeding, while simultaneously reaching up to 1.9 times higher weight gain at day 28 in extremely immature infants (<27 GA weeks) as well as overall improved growth at 2 years of age for all infants. The use of the new standardized PN solution MUC PREPARE improved nutritional supply and short- and long-term growth and reduced PN duration in very preterm infants and is considered a superior therapeutic strategy.

Read more