A Günther

Philipps University of Marburg, Marburg, Hesse, Germany

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Publications (233)1095.78 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Activation and differentiation of fibroblasts into contractile protein-expressing myofibroblasts and their acquired apoptosis-resistant phenotype are critical factors towards the development of idiopathic pulmonary fibrosis (IPF), a fatal disease characterised by distorted pulmonary structure and excessive extracellular matrix (ECM) deposition. The molecular mechanisms underlying these processes in IPF remain incompletely understood. We investigated the possible implication of aberrant overexpression and activity of histone deacetylases (HDACs) in IPF. Methods: We analysed lung tissues from patients with sporadic IPF (n=26) and non-diseased control lungs (n=16) for expression of class I and II HDACs. Primary IPF fibroblasts were treated with HDAC inhibitors (HDACi) LBH589 or valproic acid (VPA). Results: Compared to control lungs, protein levels of class I (HDAC1, HDAC2, HDAC3, HDAC8) and class II HDACs (HDAC4, HDAC 5, HDAC 7, HDAC 9) were significantly elevated in IPF lungs. Using immunohistochemistry, strong induction of nearly all HDAC enzymes was observed in myofibroblasts of fibroblast foci and in abnormal bronchiolar basal cells at sites of aberrant re-epithelialisation in IPF lungs, but not in controls. Treatment of primary IPF fibroblasts with the pan-HDACi LBH589 resulted in significantly reduced expression of genes associated with ECM synthesis, proliferation and cell survival, as well as in suppression of HDAC7, and was paralleled by induction of endoplasmic reticulum stress and apoptosis. The profibrotic and apoptosis-resistant phenotype of IPF fibroblasts was also partly attenuated by the class I HDACi VPA. Conclusions: Aberrant overexpression of HDACs in basal cells of IPF lungs may contribute to the bronchiolisation process in this disease. Similarly, generation and apoptosis resistance of IPF fibroblasts are mediated by enhanced activity of HDAC enzymes. Therefore, pan-HDAC inhibition by LBH589 may present a novel therapeutic option for patients with IPF.
    Thorax 09/2015; DOI:10.1136/thoraxjnl-2014-206411 · 8.29 Impact Factor
  • Philipp Markart · Andreas Günther
    09/2015; 7(4):21-22. DOI:10.1007/s15033-015-0185-9
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    ABSTRACT: Spirometry is a highly standardized method which allows to measure the forced vital capacity (FVC) with high precision and reproducibility. In patients with IPF FVC is directly linked to the disease process which is characterized by scaring of alveoli and shrinkage of the lungs. Consequently, there is ample evidence form clinical studies that the decline of FVC over time is consistently associated with mortality in IPF. As for the first time effective drugs for the treatment of IPF are available it becomes obvious that in studies which could demonstrate that the drug reduces FVC decline, a numerical effect on mortality was also observed, while in one study where a significant effect on FVC decline was missed, there was also no change in mortality. Based on these studies FVC decline is a validated surrogate of mortality in IPF. It is concluded that FVC decline is not only accepted as an endpoint of clinical treatment trials in IPF but is also valid as a patient related outcome parameter which should be considered for the assessment of the efficacy of an IPF drug. © Georg Thieme Verlag KG Stuttgart · New York.
    Pneumologie 07/2015; 69(8). DOI:10.1055/s-0034-1392602
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    ABSTRACT: The ubiquitin-proteasome system is critical for maintenance of protein homeostasis by degrading polyubiquitinated proteins in a spatially and timely controlled manner. Cell and protein homeostasis are altered upon pathological tissue remodelling. Dysregulation of the proteasome has been reported for several chronic diseases of the heart, brain, and lung. We hypothesized that proteasome function is altered upon fibrotic lung remodelling, thereby contributing to the pathogenesis of idiopathic pulmonary fibrosis (IPF). To investigate proteasome function during myofibroblast differentiation, we treated lung fibroblasts with TGF-β and examined proteasome composition and activity. For in vivo analysis, we used mouse models of lung fibrosis and fibrotic human lung tissue. We demonstrate that induction of myofibroblast differentiation by TGF-β involves activation of the 26S proteasome, which is critically dependent on the regulatory subunit Rpn6. Silencing of Rpn6 in primary human lung fibroblasts counteracted TGF-β-induced myofibroblast differentiation. Activation of the 26S proteasome and increased expression of Rpn6 was detected during bleomycin-induced lung remodelling and fibrosis. Importantly, Rpn6 is overexpressed in myofibroblasts and basal cells of the brochiolar epithelium in lungs of patients with IPF, which is accompanied by enhanced protein polyubiquitination. Our study identifies Rpn6-dependent 26S proteasome activation as an essential feature of myofibroblast differentiation in vitro and in vivo and suggests an important role in IPF pathogenesis.
    American Journal of Respiratory and Critical Care Medicine 07/2015; DOI:10.1164/rccm.201412-2270OC · 13.00 Impact Factor
  • Pneumologie 07/2015; 69(07). DOI:10.1055/s-0035-1556650
  • M Korfei · D Klaus · D Stelmaszek · I Henneke · W Seeger · A Guenther
    Pneumologie 07/2015; 69(07). DOI:10.1055/s-0035-1556649
  • I Shalashova · M Hühn · C Ruppert · O Klymenko · I Henneke · A Günther
    Pneumologie 07/2015; 69(07). DOI:10.1055/s-0035-1556651
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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 · 3.09 Impact Factor
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    ABSTRACT: Proteases have been shown to degrade airway mucin proteins and to damage the epithelium impairing mucociliary clearance. There are increased proteases in the COPD airway but changes in protease-antiprotease balance and mucin degradation have not been investigated during the course of a COPD exacerbation. We hypothesized that increased protease levels would lead to mucin degradation in acute COPD exacerbations. We measured neutrophil elastase (NE) and alpha 1 protease inhibitor (A1-PI) levels using immunoblotting, and conducted protease inhibitor studies, zymograms, elastin substrate assays and cigarette smoke condensate experiments to evaluate the stability of the gel-forming mucins, MUC5AC and MUC5B, before and 5-6 weeks after an acute pulmonary exacerbation of COPD (n = 9 subjects). Unexpectedly, mucin concentration and mucin stability were highest at the start of the exacerbation and restored to baseline after 6 weeks. Consistent with these data, immunoblots and zymograms confirmed decreased NE concentration and activity and increased A1-PI at the start of the exacerbation. After recovery there was an increase in NE activity and a decrease in A1-PI levels. In vitro, protease inhibitor studies demonstrated that serine proteases played a key role in mucin degradation. Mucin stability was further enhanced upon treating with cigarette smoke condensate (CSC). There appears to be rapid consumption of secreted proteases due to an increase in antiproteases, at the start of a COPD exacerbation. This leads to increased mucin gel stability which may be important in trapping and clearing infectious and inflammatory mediators, but this may also contribute acutely to mucus retention.
    Respiratory research 07/2015; 16(1):85. DOI:10.1186/s12931-015-0247-x · 3.09 Impact Factor
  • Philipp Markart · Andreas Günther
    06/2015; 7(3):21-22. DOI:10.1007/s15033-015-0137-4
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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: Respiratory tract infections are common in patients suffering from pulmonary fibrosis. The interplay between bacterial infection and fibrosis is characterised poorly. To assess the effect of Gram-positive bacterial infection on fibrosis exacerbation in mice. Fibrosis progression in response to Streptococcus pneumoniae was examined in two different mouse models of pulmonary fibrosis. We demonstrate that wild-type mice exposed to adenoviral vector delivery of active transforming growth factor-β1 (TGFß1) or diphteria toxin (DT) treatment of transgenic mice expressing the DT receptor (DTR) under control of the surfactant protein C (SPC) promoter (SPC-DTR) to induce pulmonary fibrosis developed progressive fibrosis following infection with Spn, without exhibiting impaired lung protective immunity against Spn. Antibiotic treatment abolished infection-induced fibrosis progression. The cytotoxin pneumolysin (Ply) of Spn caused this phenomenon in a TLR4-independent manner, as Spn lacking Ply (SpnΔply) failed to trigger progressive fibrogenesis, whereas purified recombinant Ply did. Progressive fibrogenesis was also observed in AdTGFβ1-exposed Ply-challenged TLR4 KO mice. Increased apoptotic cell death of alveolar epithelial cells along with an attenuated intrapulmonary release of antifibrogenic prostaglandin E2 was found to underlie progressive fibrogenesis in Ply-challenged AdTGFβ1-exposed mice. Importantly, vaccination of mice with the non-cytotoxic Ply derivative B (PdB) substantially attenuated Ply-induced progression of lung fibrosis in AdTGFβ1-exposed mice. Our data unravel a novel mechanism by which infection with Spn through Ply release induces progression of established lung fibrosis, which can be attenuated by protein-based vaccination of mice. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Thorax 05/2015; 70(7). DOI:10.1136/thoraxjnl-2014-206420 · 8.29 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; 309(1):ajplung.00279.2014. DOI:10.1152/ajplung.00279.2014 · 4.08 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 · 9.67 Impact Factor
  • Philipp Markart · Malgorzata Wygrecka · Andreas Günther
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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
  • Atemwegs- und Lungenkrankheiten 04/2015; 41(4):188-193. DOI:10.5414/ATX02031
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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 · 4.08 Impact Factor
  • Friedrich Grimminger · Andreas Günther · Carlo Vancheri
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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 · 7.64 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

Publication Stats

4k Citations
1,095.78 Total Impact Points


  • 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
  • 1992–2015
    • Justus-Liebig-Universität Gießen
      • • Department of Internal Medicine
      • • Faculty of Medicine
      Giessen, Hesse, Germany
  • 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