A Günther

Philipps University of Marburg, Marburg, Hesse, Germany

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Publications (221)1029.98 Total impact

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    ABSTRACT: Recent clinical studies show that tyrosine kinase inhibitors slow the rate of lung function decline and decrease the number of acute exacerbations in patients with Idiopathic Pulmonary Fibrosis (IPF). However, in the murine bleomycin model of fibrosis, not all tyrosine kinase signaling is detrimental. Exogenous ligands Fibroblast Growth Factor (FGF) 7 and 10 improve murine lung repair and increase survival after injury via tyrosine kinase FGF receptor 2b-signaling. Therefore, the level and location of FGF/FGFR expression as well as the exogenous effect of the most highly expressed FGFR2b ligand, FGF1, was analyzed on human lung fibroblasts. FGF ligand and receptor expression was evaluated in donor and IPF whole lung homogenates using western blotting and qPCR. Immunohistochemistry for FGF1 and FGFR1/2/3/4 were performed on human lung tissue. Lastly, the effects of FGF1, a potent, multi-FGFR ligand, were studied on primary cultures of IPF and non-IPF donor fibroblasts. Western blots for pro-fibrotic markers, proliferation, FACS for apoptosis, transwell assays and MetaMorph analyses on cell cultures were performed. Whole lung homogenate analyses revealed decreased FGFR b-isoform expression, and an increase in FGFR c-isoform expression. Of the FGFR2b-ligands, FGF1 was the most significantly increased in IPF patients; downstream targets of FGF-signaling, p-ERK1/2 and p-AKT were also increased. Immunohistochemistry revealed FGF1 co-localization within basal cell sheets, myofibroblast foci, and Surfactant protein-C positive alveolar epithelial type-II cells as well as co-localization with FGFR1, FGFR2, FGFR3, FGFR4 and myofibroblasts expressing the migratory marker Fascin. Both alone and in the presence of heparin, FGF1 led to increased MAPK-signaling in primary lung fibroblasts. While smooth muscle actin was unchanged, heparin + FGF1 decreased collagen production in IPF fibroblasts. In addition, FGF1 + heparin increased apoptosis and cell migration. The FGFR inhibitor (PD173074) attenuated these effects. Strong expression of FGF1/FGFRs in pathogenic regions of IPF suggest that aberrant FGF1-FGFR signaling is increased in IPF patients and may contribute to the pathogenesis of lung fibrosis by supporting fibroblast migration and increased MAPK-signaling.
    Respiratory research 07/2015; 16(1):83. DOI:10.1186/s12931-015-0242-2 · 3.38 Impact Factor
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    ABSTRACT: Impaired immune function contributes to the development of chronic obstructive pulmonary disease (COPD). Disease progression is further exacerbated by pathogen infections due to impaired immune responses. Elimination of infected cells is achieved by cytotoxic CD8(+) T cells that are activated by MHC I-mediated presentation of pathogen-derived antigenic peptides. The immunoproteasome, a specialized form of the proteasome, improves generation of antigenic peptides for MHC I presentation thereby facilitating anti-viral immune responses. However, immunoproteasome function in the lung has not been investigated in detail yet. In this study, we comprehensively characterized the function of immunoproteasomes in the human and murine lung. Parenchymal cells of the lung express low constitutive levels of immunoproteasomes, while they are highly and specifically expressed in alveolar macrophages. Immunoproteasome expression is not altered in whole lung tissue of COPD patients. Novel activity-based probes and native gel analysis revealed that immunoproteasome activities are specifically and rapidly induced by IFNγ treatment in respiratory cells in vitro and by virus infection of the lung in mice. Our results suggest that the lung is potentially capable of mounting an immunoproteasome-mediated efficient adaptive immune response to intracellular infections.
    Scientific Reports 05/2015; 5:10230. DOI:10.1038/srep10230 · 5.58 Impact Factor
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    ABSTRACT: Chronic injury of alveolar epithelial type II cells (AE2 cells) represents a key event in the development of lung fibrosis in animal models and in humans, such as Idiopathic Pulmonary Fibrosis (IPF). Intratracheal delivery of amiodarone to mice results in a profound injury and macroautophagy dependent apoptosis of AE2 cells. Increased autophagy manifested in AE2 cells by disturbances of the intracellular surfactant . Hence, we hypothesized that ultrastructural alterations of the intracellular surfactant pool are signs of epithelial stress correlating with the severity of fibrotic remodeling. Using design based stereology the amiodarone model of pulmonary fibrosis in mice was characterized at the light and ultrastructural level during progression. Mean volume of AE2 cells, volume of lamellar bodies per AE2 cell and mean size of lamellar bodies were correlated to structural parameters reflecting severity of fibrosis like collagen content. Within 2 weeks amiodarone leads to an increase in septal wall thickness and a decrease in alveolar numbers due to irreversible alveolar collapse associated with alveolar surfactant dysfunction. Progressive hypertrophy of AE2 cells, increase in mean individual size and total volume of lamellar bodies per AE2 cell were observed. A high positive correlation of these AE2 cell-related ultrastructural changes and the deposition of collagen fibrils within septal walls were established. Qualitatively, similar alterations could be found in IPF samples with mild to moderate fibrosis. We conclude that ultrastructural alterations of AE2 cells including the surfactant system are tightly correlated with the progression of fibrotic remodeling. Copyright © 2014, American Journal of Physiology - Lung Cellular and Molecular Physiology.
    AJP Lung Cellular and Molecular Physiology 05/2015; DOI:10.1152/ajplung.00279.2014 · 4.04 Impact Factor
  • Medical Informatics Europe 2015, Madrid; 05/2015
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a devastating disease, and its pathogenic mechanisms remain incompletely understood. Peroxisomes are known to be important in ROS and proinflammatory lipid degradation, and their deficiency induces liver fibrosis. However, altered peroxisome functions in IPF pathogenesis have never been investigated. By comparing peroxisome-related protein and gene expression in lung tissue and isolated lung fibroblasts between human control and IPF patients, we found that IPF lungs exhibited a significant down-regulation of peroxisomal biogenesis and metabolism (e.g., PEX13p and acyl-CoA oxidase 1). Moreover, in vivo the bleomycin-induced down-regulation of peroxisomes was abrogated in transforming growth factor beta (TGF-β) receptor II knockout mice indicating a role for TGF-β signaling in the regulation of peroxisomes. Furthermore, in vitro treatment of IPF fibroblasts with the profibrotic factors TGF-β1 or tumor necrosis factor alpha (TNF-α) was found to down-regulate peroxisomes via the AP-1 signaling pathway. Therefore, the molecular mechanisms by which reduced peroxisomal functions contribute to enhanced fibrosis were further studied. Direct down-regulation of PEX13 by RNAi induced the activation of Smad-dependent TGF-β signaling accompanied by increased ROS production and resulted in the release of cytokines (e.g., IL-6, TGF-β) and excessive production of collagen I and III. In contrast, treatment of fibroblasts with ciprofibrate or WY14643, PPAR-α activators, led to peroxisome proliferation and reduced the TGF-β-induced myofibroblast differentiation and collagen protein in IPF cells. Taken together, our findings suggest that compromised peroxisome activity might play an important role in the molecular pathogenesis of IPF and fibrosis progression, possibly by exacerbating pulmonary inflammation and intensifying the fibrotic response in the patients.
    Proceedings of the National Academy of Sciences 04/2015; 112(16). DOI:10.1073/pnas.1415111112 · 9.81 Impact Factor
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    ABSTRACT: Die idiopathische pulmonale Fibrose (IPF) ist die aggressivste und gleichzeitig eine der häufigsten interstitiellen Lungenerkrankungen. Betroffen sind meist ältere Menschen, oft frühere Raucher. Die Ätiologie ist unbekannt. Die Erkrankung ist auf die Lunge begrenzt, Leitsymptome sind Dyspnoe und trockener Husten. Pathogenetisch gilt die IPF als eine epithelial-fibroblastäre Erkrankung. Die Diagnostik umfasst den Ausschluss interstitieller Lungenerkrankungen bekannter Ätiologie, das Thorax-Computertomogramm, die Bronchoskopie mit Differenzialzellbild der bronchoalveolären Lavage und ggf. die chirurgische Lungenbiopsie. Pharmakologisch wird Pirfenidon zur Behandlung von IPF-Patienten mit leichter bis mittlerer Krankheitsschwere eingesetzt. Mit Nintedanib wurde aktuell eine zweite Substanz zur Behandlung der IPF zugelassen. Die akute Exazerbation ist eine häufige Komplikation mit hoher Letalität.
    04/2015; 7(2):29-36. DOI:10.1007/s15033-014-0003-9
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    ABSTRACT: Fibroblast growth factors (Fgfs) mediate organ repair. Lung epithelial cell overexpression of Fgf10 post-bleomycin injury is both protective and therapeutic, characterized by increased survival and attenuated fibrosis. Exogenous administration of FGF7 (Palifermin) also showed prophylactic survival benefits in mice. The role of endogenous Fgfr2b ligands upon bleomycin-induced lung fibrosis is still elusive. This study reports the expression of endogenous Fgfr2b ligands, receptors and signaling targets in wild type mice following bleomycin lung injury. In addition, the impact of attenuating endogenous Fgfr2b-ligands following bleomycin-induced fibrosis was tested using a doxycycline (dox)-based inducible, soluble, dominant-negative form of the Fgfr2b receptor. Double transgenic (DTG) Rosa26(rtTA/+);tet(O)solFgfr2b mice were validated for the expression and activity of soluble Fgfr2b (failure to regenerate maxillary incisors, attenuated recombinant FGF7 signal in the lung). As previously reported, no defects in lung morphometry were detected in DTG (+dox) mice exposed from post-natal (PN) 1 through PN105. Female single transgenic (STG) and DTG mice were subjected to various levels of bleomycin injury (1.0, 2.0, and 3.0U/kg). Fgfr2b ligands were attenuated either throughout injury (d0-d11; d0-28) or during later stages (d6-d28 and d14-d28). No significant changes in survival, weight, lung function, confluent areas of fibrosis, or hydroxyproline deposition were detected in DTG mice. These results indicate that endogenous Fgfr2b ligands do not significantly protect against bleomycin injury, nor do they expedite the resolution of bleomycin lung induced injury in mice. Copyright © 2014, American Journal of Physiology - Lung Cellular and Molecular Physiology.
    AJP Lung Cellular and Molecular Physiology 03/2015; 308(10):ajplung.00291.2014. DOI:10.1152/ajplung.00291.2014 · 4.04 Impact Factor
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a median survival time from diagnosis of 2-3 years. Although the pathogenic pathways have not been fully elucidated, IPF is believed to be caused by persistent epithelial injury in genetically susceptible individuals. Tyrosine kinases are involved in a range of signalling pathways that are essential for cellular homeostasis. However, there is substantial evidence from in vitro studies and animal models that receptor tyrosine kinases, such as the platelet-derived growth factor receptor, vascular endothelial growth factor receptor and fibroblast growth factor receptor, and non-receptor tyrosine kinases, such as the Src family, play critical roles in the pathogenesis of pulmonary fibrosis. For example, the expression and release of tyrosine kinases are altered in patients with IPF, while specific tyrosine kinases stimulate the proliferation of lung fibroblasts in vitro. Agents that inhibit tyrosine kinases have shown anti-fibrotic and anti-inflammatory effects in animal models of pulmonary fibrosis. Recently, the tyrosine kinase inhibitor nintedanib has shown positive results in two phase III trials in patients with IPF. Here, we summarise the evidence for involvement of specific tyrosine kinases in the pathogenesis of IPF and the development of tyrosine kinase inhibitors as treatments for IPF. Copyright ©ERS 2015.
    European Respiratory Journal 03/2015; 45(5). DOI:10.1183/09031936.00149614 · 7.13 Impact Factor
  • Phillipp Markart, Andreas Günther
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    ABSTRACT: Hintergrund und Fragestellung: Das GAP-Modell ist ein klinisches Risiko-Vorhersagemodell, welches die Komponenten Geschlecht, Alter und Lungenphysiologie (GAP) umfasst [1]. Es wurde kürzlich bei Patienten mit Idiopathischer Pulmonaler Fibrose (IPF) validiert [1]. In der vorliegenden Studie wurde nun untersucht, ob das GAP-Modell die Mortalität auch bei anderen Formen chronisch interstitieller Lungenerkrankungen (ILD) akkurat voraussagen kann.Patienten und Methoden: Die folgenden Patientengruppen wurden einbezogen: IPF (n=307), chronische exogen allergische Alveolitis (n=206), Kollagenose-assoziierte ILD (n=281), idiopathische nicht spezifische interstitielle Pneumonie (NSIP; n=45) und unklassifizierbare ILD (n=173). Das GAP-Modell wurde mit neuen Vorhersagemodellen bei jeder der ILD-Untergruppen und in der kombinierten Kohorte verglichen.Ergebnisse und Schlussfolgerung: Das GAP-Modell konnte die Mortalität in allen ILD-Subtypen akkurat vorhersagen (C-Index 74,6 in der kombinierten Koho ...
    03/2015; 7(1):12-13. DOI:10.1007/s15033-015-0055-5
  • Pneumologie 02/2015; 69(S 01). DOI:10.1055/s-0035-1544823
  • American Journal of Respiratory and Critical Care Medicine 01/2015; 191(1):110-3. DOI:10.1164/rccm.201406-1106LE · 11.99 Impact Factor
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    ABSTRACT: Hemeoxygenase-1 (HO-1), an inducible heat shock protein, is upregulated in response to multiple cellular insults via oxidative stress, lipopolysaccharides (LPS) and hypoxia. In this study, we investigated in vitro the role of toll-like receptor 4 (TLR4), hypoxia-inducible factor-1α (HIF-1α) and iron on HO-1 expression in cystic fibrosis (CF). Immunohistochemical analysis of TLR4, HO-1, ferritin and HIF-1α were performed on lung sections of CFTR-/- and wildtype mice. CFBE41o- and 16HBE14o- cell lines were employed for in vitro analysis via immunoblotting, immunofluorescence, real-time PCR, luciferase reporter gene analysis and iron quantification. We observed a reduced TLR4, HIF-1α, HO-1, and ferritin in CFBE41o- cell line and CF mice. Knockdown studies using TLR4-siRNA in 16HBE14o- revealed significant decrease of HO-1, confirming the role of TLR4 in HO-1 downregulation. Inhibition of HO-1 using tin protoporphyrin in 16HBE14o- cells resulted in increased iron levels suggesting a probable role of HO-1 in iron accumulation. Additionally, sequestration of excess iron using iron chelators resulted in increased HRE response in CFBE41o- and 16HBE14o- implicating a role of iron in HIF-1α stabilization and HO-1. To conclude, our in vitro results demonstrate that multiple regulatory factors such as impaired TLR4 surface expression, increased intracellular iron and decreased HIF-1α downregulates HO-1 expression in CFBE41o- cells.
    AJP Lung Cellular and Molecular Physiology 09/2014; DOI:10.1152/ajplung.00167.2014 · 4.04 Impact Factor
  • Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS), Göttingen; 09/2014
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    ABSTRACT: Amiodarone (AD) is a highly efficient antiarrhythmic drug with potentially serious side effects. Severe pulmonary toxicity is reported in patients receiving AD even at low doses, and may cause interstitial pneumonia as well as lung fibrosis. Apoptosis of alveolar epithelial type II cells (AECII) has been suggested to play an important role in this disease. In the current study, we aimed to establish a murine model of AD induced lung fibrosis and analyze surfactant homeostasis, lysosomal and endoplasmic reticulum stress in this model. AD/ vehicle was instilled intratracheally into C57BL/6 mice, which were sacrificed on days 7, 14, 21 and 28. Extent of lung fibrosis development was assessed by trichrome staining and hydroxyproline measurement. Cytotoxicity was assessed by lactate dehydrogenase assay. Phospholipids (PL) were analyzed by mass spectrometry. Surfactant proteins (SP) and markers for apoptosis, lysosomal & ER stress were studied by western blotting and immunohistochemistry. AECII morphology was evaluated by electron microscopy. Extensive lung fibrosis and AECII hyperplasia was observed in AD treated mice already at day7. Surfactant PL and SP accumulated in AECII over time. In parallel, induction of apoptosis, lysosomal and ER stress was encountered in AECII of mice lungs and in MLE12 cells treated with AD. In vitro, si RNA mediated knock down of cathepsin D did not alter the AD induced apoptotic response. Our data suggest that mice exposed to intratracheal AD develop severe pulmonary fibrosis, exhibit extensive surfactant alterations and cellular stress, but AD induced AECII apoptosis is not mediated primarily via cathepsin D.
    Toxicological Sciences 08/2014; 142(1). DOI:10.1093/toxsci/kfu177 · 4.48 Impact Factor
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    ABSTRACT: The current study investigated the mechanisms involved in the process of biophysical inhibition of pulmonary surfactant by polymeric nanoparticles0020(NP). The minimal surface tension of diverse synthetic surfactants was monitored in the presence of bare and surface-decorated (i.e. poloxamer 407) sub-100 nm poly(lactide) NP. Moreover, the influence of NP on surfactant composition (i.e. surfactant protein (SP) content) was studied. Dose-elevations of SP advanced the biophysical activity of the tested surfactant preparation. SP-C supplemented phospholipid mixtures (PLM-C) were shown to be more susceptible to biophysical inactivation by bare NP than PLM-B and PLM-B/C. Surfactant function was hindered due to a drastic depletion of the SP content upon contact with bare NP. By contrast, surface-modified NP were capable to circumvent unwanted surfactant inhibition. Surfactant constitution influences the extent of biophysical inhibition by polymeric NP. Steric shielding of the NP surface minimizes unwanted NP-surfactant interactions, which represents an option for the development of surfactant-compatible nanomedicines.
    Acta Biomaterialia 07/2014; 10(11). DOI:10.1016/j.actbio.2014.07.026 · 5.68 Impact Factor
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    ABSTRACT: Rationale: Idiopathic pulmonary fibrosis (IPF) and bleomycin-induced pulmonary fibrosis are associated with surfactant-system dysfunction, alveolar collapse (derecruitment), and collapse induration (irreversible collapse). These events play undefined roles in the loss of lung function. Objective: To quantify how surfactant inactivation, alveolar collapse and collapse induration lead to degradation of lung function. Methods and measurements: Design-based stereology and invasive pulmonary function tests were performed 1, 3, 7, and 14 days (D) following intratracheal bleomycin-instillation in rats. The number and size of open alveoli was correlated to mechanical properties. Main Results: Active surfactant subtypes declined by D1, associated with a progressive alveolar derecruitment and a decrease in compliance. Alveolar epithelial damage was more pronounced in closed alveoli compared to ventilated alveoli. Collapse induration occurred on D7 and D14 as indicated by collapsed alveoli overgrown by a hyperplastic alveolar epithelium. This pathophysiology was also observed for the first time in human IPF lung explants. Prior to the onset of collapse induration, distal airspaces were easily recruited, and lung elastance could be kept low after recruitment by positive end-expiratory pressure (PEEP). At later time points the recruitable fraction of the lung was reduced by collapse induration, causing elastance to be elevated at high levels of PEEP. Conclusion: Surfactant inactivation leading to alveolar collapse and subsequent collapse induration might be the primary pathway for the loss of alveoli in this animal model. Loss of alveoli is highly correlated with the degradation of lung function. Our ultrastructural observations suggest that collapse induration is important in human IPF.
    American Journal of Respiratory Cell and Molecular Biology 07/2014; 52(2). DOI:10.1165/rcmb.2014-0078OC · 4.11 Impact Factor
  • Pneumologie 06/2014; 68(06). DOI:10.1055/s-0034-1376807
  • Pneumologie 06/2014; 68(06). DOI:10.1055/s-0034-1376792
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    ABSTRACT: Amiodarone (AD) is an iodinated benzofuran derivative, especially known for its antiarrhythmic properties. It exerts serious side-effects even in patients receiving low doses. AD is well-known to induce apoptosis of type II alveolar epithelial cells (AECII), a mechanism that has been suggested to play an important role in AD-induced lung fibrosis. The precise molecular mechanisms underlying this disease are however still unclear. Because of its amphiphilic nature, AD becomes enriched in the lysosomal compartments, affecting the general functions of these organelles. Hence, in this study, we aimed to assess the role of autophagy, a lysosome dependent homeostasis mechanism, in driving AECII apoptosis in response to AD. In vitro, AD-treated MLE12 and primary AECII cells showed increased proSP-C and LC3B positive vacuolar structures and underwent LC3B-dependent apoptosis. In addition, AD-induced autophagosome-lysosome fusion and increased autophagy flux were observed. In vivo, in C57BL/6 mice, LC3B was localized at the limiting membrane of lamellar bodies, which were closely connected to the autophagosomal structures in AECIIs. Our data suggest that AD causes activation of macroautophagy in AECIIs and extensive autophagy-dependent apoptosis of alveolar epithelial cells. Targeting the autophagy pathway may therefore represent an attractive treatment modality in AD-induced lung fibrosis. This article is protected by copyright. All rights reserved.
    Pneumologie 06/2014; 68(06). DOI:10.1055/s-0034-1376801

Publication Stats

4k Citations
1,029.98 Total Impact Points

Institutions

  • 2015
    • Philipps University of Marburg
      Marburg, Hesse, Germany
  • 2013–2015
    • Vitos Gießen-Marburg
      Giessen, Hesse, Germany
  • 2009–2015
    • Universitätsklinikum Gießen und Marburg
      • Klinik für Medizinische Virologie
      Marburg, Hesse, Germany
    • University of Southern California
      • Department of Surgery
      Los Angeles, CA, United States
  • 1994–2015
    • Justus-Liebig-Universität Gießen
      • • Department of Internal Medicine
      • • Faculty of Medicine
      Gieben, Hesse, Germany
  • 2012–2014
    • HELIOS Klinikum Emil von Behring
      • Klinik für Kinder- und Jugendmedizin
      Berlin Steglitz Zehlendorf, Berlin, Germany
  • 2008
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
  • 2007
    • Actelion Pharmaceuticals Ltd
      Allschwil, Basel-Landschaft, Switzerland