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Stöger Lab

Dynamics of Pulmonary Inflammation

We want to understand the circumstances that impair pulmonary inflammation in a way to cause a long-term damage of the lung. Our goals are therapeutic nanoparticles for pulmonary application and the respiratory safety of engineered nanoparticles.

We want to understand the circumstances that impair pulmonary inflammation in a way to cause a long-term damage of the lung. Our goals are therapeutic nanoparticles for pulmonary application and the respiratory safety of engineered nanoparticles.

Our Key Questions

 

  • Which circumstances impair pulmonary inflammation in a way to cause a long-term damage of the lung?
  • Which factors determine the transition from acute to chronic inflammation. How are alveolar macrophages involved?
  • What makes some environmental stimuli cause a persistent, non resolving inflammtion while other stimuli only initiate a transient irritation?
  • Particularly, which material properties of inhaled particles determine the particle-triggered course of inflammation?

Image: human lung organoids grown from induced stem cells

     

     

     

    Inflammation - blessing and curse

    Inflammation is a very dynamic biological reaction of the tissues in response to any stimuli that is harmful to the body. To prevent unnecessary tissue damage, the acute inflammatory response must be actively terminated and resolved when no longer needed. When the inflammation lasts much longer than normal or even becomes chronic, it is usually a major destruction and replacement of the cells within the tissue suffering the inflammation. Persistent or chronic inflammation might thus been seen as a failure of resolution, and often present in patients with chronic lung diseases such as COPD. It may also lead to an imbalance in production of cytokines and growth factors and thereby trigger abnormal wound-healing responses characteristic for the fatal disorder: pulmonary fibrosis.

    Image: Human iPSC generated lung organoid (nuclei in cyan) and fibroblasts (red) in co-culture

     

    Scientists at Stöger Lab

    Portrait Camille Barro LHI

    Camille Barro

    PhD Student
    Deng_Jiating_Portrait

    Jiating Deng

    PhD Student
    Hagl_Beate_Portrait

    Beate Hagl

    Principal Investigator
    Portrait Lianyong Han LHI

    Lianyong Han

    Postdoc
    Huzain_Osama_Portrait

    Osama Huzain

    PhD Student
    Kutschke_David_Porträt_LHI

    David Kutschke

    Technical Assistant
    Ren_Hongyu_Porträt_LHI

    Hongyu Ren

    PhD Student
    Portrait Yasmin Shaalan LHI

    Yasmin Shaalan

    PhD Student

    Publications

    2024, Wissenschaftlicher Artikel in Nature Communications

    LungVis 1.0: An automatic AI-powered 3D imaging ecosystem unveils spatial profiling of nanoparticle delivery and acinar migration of lung macrophages.

    Targeted (nano-)drug delivery is essential for treating respiratory diseases, which are often confined to distinct lung regions. However, spatio-temporal profiling of drugs or nanoparticles (NPs) and their interactions with lung macrophages remains unresolved. Here, we present LungVis 1.0, an AI-powered imaging ecosystem that integrates light sheet fluorescence microscopy with deep learning-based image analysis pipelines to map NP deposition and dosage holistically and quantitatively across bronchial and alveolar (acinar) regions in murine lungs for widely-used bulk-liquid and aerosol-based delivery methods. We demonstrate that bulk-liquid delivery results in patchy NP distribution with elevated bronchial doses, whereas aerosols achieve uniform deposition reaching distal alveoli. Furthermore, we reveal that lung tissue-resident macrophages (TRMs) are dynamic, actively patrolling and redistributing NPs within alveoli, contesting the conventional paradigm of TRMs as static entities. LungVis 1.0 provides an advanced framework for exploring pulmonary delivery dynamics and deepening insights into TRM-mediated lung immunity.

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    2024, Wissenschaftlicher Artikel in Microbiology and Immunology

    First detection and biological characterization of an avian metaavulavirus 8 isolated from a migratory swan goose in Qinghai Lake, Northwest China.

    Avian metaavulavirus 8 (AMAV-8), formerly known as avian paramyxovirus 8 (APMV-8), has been detected sporadically in wild birds worldwide since it was first identified in a Canadian goose in 1976. However, the presence of AMAV-8 in birds has never been reported in China. To understand the epidemiological situation of AMAV-8 and its ability to infect chickens, we conducted a surveillance study and in vivo analysis of the AMAV-8 isolate identified in total of 14,909 clinical samples collected from wild and domestic birds from 2014 to 2022 in China. However, in 2017, only one AMAV-8 virus (Y7) was successful isolated from the fresh droppings of a migratory swan goose in Qinghai Lake in Northwest China. Thereafter, we report the complete genome sequence of the Y7 strain with a genome length of 15,342 nucleotides and the Y7 isolate was genetically closely-related to wild bird-origin AMAV-8 viruses previously circulated in the United States, Japan, and Kazakhstan. Furthermore, AMAV-8 infections of one-day-old specific pathogen-free (SPF) chicks did not induce any clinical signs over the entire observation period but was associated with viral shedding for up to 8 days. Interestingly, although all birds infected with the Y7 strain seroconverted within the first week of infection, virus replication was only detected in the trachea but not in other tissues such as the brain, lung, or heart. Here, we report the complete genome, genetic and biological characterization, replication and pathogenicity analysis in vivo and first detection of AMAV-8 in China.

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    2024, Wissenschaftlicher Artikel in Advanced science

    The eATP/P2×7R axis drives quantum dot-nanoparticle induced neutrophil recruitment in the pulmonary microcirculation.

    Exposure to nanoparticles (NPs) is frequently associated with adverse cardiovascular effects. In contrast, NPs in nanomedicine hold great promise for precise lung-specific drug delivery, especially considering the extensive pulmonary capillary network that facilitates interactions with bloodstream-suspended particles. Therefore, exact knowledge about effects of engineered NPs within the pulmonary microcirculation are instrumental for future application of this technology in patients. To unravel the real-time dynamics of intravenously delivered NPs and their effects in the pulmonary microvasculature, we employed intravital microscopy of the mouse lung. Only PEG-amine-QDs, but not carboxyl-QDs triggered rapid neutrophil recruitment in microvessels and their subsequent recruitment to the alveolar space and was linked to cellular degranulation, TNF-α, and DAMP release into the circulation, particularly eATP. Stimulation of the ATP-gated receptor P2X7R induced expression of E-selectin on microvascular endothelium thereby mediating the neutrophilic immune response. Leukocyte integrins LFA-1 and MAC-1 facilitated adhesion and decelerated neutrophil crawling on the vascular surface. In summary, this study unravels the complex cascade of neutrophil recruitment during NP-induced sterile inflammation. Thereby we demonstrate novel adverse effects for NPs in the pulmonary microcirculation and provide critical insights for optimizing NP-based drug delivery and therapeutic intervention strategies, to ensure their efficacy and safety in clinical applications.

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    2024, Wissenschaftlicher Artikel in NanoImpact

    Next generation risk assessment approaches for advanced nanomaterials: current status and future perspectives.

    This manuscript discusses the challenges of applying New Approach Methodologies (NAMs) for safe by design and regulatory risk assessment of advanced nanomaterials (AdNMs). The authors propose a framework for Next Generation Risk Assessment of AdNMs involving NAMs that is aligned to the conventional risk assessment paradigm. This framework is exposure-driven, endpoint-specific, makes best use of pre-existing information, and can be implemented in tiers of increasing specificity and complexity of the adopted NAMs. The tiered structure of the approach, which effectively combines the use of existing data with targeted testing will allow safety to be assessed cost-effectively and as far as possible with an even more limited use of vertebrates. The regulatory readiness of state-of-the-art emerging NAMs is assessed in terms of Transparency, Reliability, Accessibility, Applicability, Relevance and Completeness, and their relevance for AdNMs are discussed in relation to each step of the risk assessment paradigm along with providing perspectives for future developments in the respective scientific and regulatory areas.

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    2024, Wissenschaftlicher Artikel in Avian Pathology

    The first report and biological characterization of Avian Orthoavulavirus 16 in wild migratory waterfowl and domestic poultry in China reveal a potential threat to birds.

    AbstractThe Avulavirus within the family Paramyxoviridae includes at least 22 different species, and is known to cause different types of infections and even be fatal in multiple avian species. There is limited knowledge of the genetic and biological information of Avulavirus species -2 to 22 in domestic and wild birds and the disease significance of these viruses in birds is not fully determined, although as many as 10 new distinct species have been identified from wild birds and domestic poultry around the world in the last decade. This study aimed to use PCR, virus isolation, and sequencing to genetically and biologically characterize Avian Orthoavulavirus 16 (AOAV-16) in wild birds and domestic poultry collected from different locations in China between 2014 and 2022. Of five isolated AOAV-16 strains (Y1 to Y5), only the Y4 strain had a hemagglutination (HA)-negative result. All of these isolates were low virulent viruses for chickens, except Y3 which was detected simultaneously with avian influenza virus (AIV) of H9N2 subtype. Furthermore, at least four different types of intergenic sequences (IGS) between the HN and L genes junction, and the recombination event as well as interspecific transmission by wild migratory birds, existed within the species AOAV-16. These findings and results of other reported AOAV-16 strains recommend strict control measures to limit contact between wild migratory birds and domestic poultry and imply potential threats to commercial poultry and even public health challenges worldwide.

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    2024, Wissenschaftlicher Artikel in Thorax

    COPD basal cells are primed towards secretory to multiciliated cell imbalance driving increased resilience to environmental stressors.

    INTRODUCTION: Environmental pollutants injure the mucociliary elevator, thereby provoking disease progression in chronic obstructive pulmonary disease (COPD). Epithelial resilience mechanisms to environmental nanoparticles in health and disease are poorly characterised. METHODS: We delineated the impact of prevalent pollutants such as carbon and zinc oxide nanoparticles, on cellular function and progeny in primary human bronchial epithelial cells (pHBECs) from end-stage COPD (COPD-IV, n=4), early disease (COPD-II, n=3) and pulmonary healthy individuals (n=4). After nanoparticle exposure of pHBECs at air-liquid interface, cell cultures were characterised by functional assays, transcriptome and protein analysis, complemented by single-cell analysis in serial samples of pHBEC cultures focusing on basal cell differentiation. RESULTS: COPD-IV was characterised by a prosecretory phenotype (twofold increase in MUC5AC+) at the expense of the multiciliated epithelium (threefold reduction in Ac-Tub+), resulting in an increased resilience towards particle-induced cell damage (fivefold reduction in transepithelial electrical resistance), as exemplified by environmentally abundant doses of zinc oxide nanoparticles. Exposure of COPD-II cultures to cigarette smoke extract provoked the COPD-IV characteristic, prosecretory phenotype. Time-resolved single-cell transcriptomics revealed an underlying COPD-IV unique basal cell state characterised by a twofold increase in KRT5+ (P=0.018) and LAMB3+ (P=0.050) expression, as well as a significant activation of Wnt-specific (P=0.014) and Notch-specific (P=0.021) genes, especially in precursors of suprabasal and secretory cells. CONCLUSION: We identified COPD stage-specific gene alterations in basal cells that affect the cellular composition of the bronchial elevator and may control disease-specific epithelial resilience mechanisms in response to environmental nanoparticles. The identified phenomena likely inform treatment and prevention strategies.

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    2024, Wissenschaftlicher Artikel in American Journal of Respiratory and Critical Care Medicine

    Inhalable textile microplastic fibers impair airway epithelial differentiation.

    RATIONALE: Microplastics are a pressing global concern and inhalation of microplastic fibers has been associated with interstitial and bronchial inflammation in flock workers. However, how microplastic fibers affect the lungs is unknown. OBJECTIVES: Our aim was to assess the effects of 12x31 µm nylon 6,6 (nylon) and 15x52 µm polyethylene terephthalate (polyester) textile microplastic fibers on lung epithelial growth and differentiation. METHODS: We used human and murine alveolar and airway-type organoids as well as air-liquid interface cultures derived from primary lung epithelial progenitor cells and incubated these with either nylon or polyester fibers or nylon leachate. In addition, mice received one dose of nylon fibers or nylon leachate and 7 days later organoid-forming capacity of isolated epithelial cells was investigated. MEASUREMENTS AND MAIN RESULTS: We observed that nylon microfibers, more than polyester, inhibited developing airway organoids and not established ones. This effect was mediated by components leaching from nylon. Epithelial cells isolated from mice exposed to nylon fibers or leachate, also formed fewer airway organoids, suggesting long-lasting effects of nylon components on epithelial cells. Part of these effects were recapitulated in human air-liquid interface cultures. Transcriptome analysis revealed upregulation of Hoxa5 post-exposure to nylon fibers. Inhibiting Hoxa5 during nylon exposure restored airway organoid formation, confirming Hoxa5's pivotal role in the effects of nylon. CONCLUSIONS: These results suggest that components leaching from nylon 6,6 may especially harm developing airways and/or airways undergoing repair and we strongly encourage to characterize both hazard of and exposure to microplastic fibers in more detail.

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    Contact

    Stöger_Tobias_FREI

    Dr. Tobias Stöger

    Team Leader