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Restored alveolar epithelial differentiation and reversed human lung fibrosis upon Notch inhibition

View ORCID ProfileRM Wasnick, View ORCID ProfileM Korfei, K Piskulak, I Henneke, View ORCID ProfileJ Wilhelm, View ORCID ProfileP Mahavadi, View ORCID ProfileD von der Beck, M Koch, I Shalashova, View ORCID ProfileO Klymenko, L Fink, H Witt, View ORCID ProfileH Hackstein, E El Agha, S Bellusci, W Klepetko, M Königshoff, O Eickelberg, T Braun, View ORCID ProfileW Seeger, C Ruppert, A Guenther
doi: https://doi.org/10.1101/580498
RM Wasnick
1Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
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M Korfei
1Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
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  • ORCID record for M Korfei
K Piskulak
1Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
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I Henneke
1Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
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J Wilhelm
1Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
10Cardio-Pulmonary Institute (CPI), 35392 Giessen, Germany
11University of Giessen and Marburg Lung Center (UGMLC); German Center for Lung Research (DZL), 35392 Giessen, Germany
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P Mahavadi
1Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
9Excellence Cluster Cardio-Pulmonary System (ECCPS), 35392 Giessen, Germany
10Cardio-Pulmonary Institute (CPI), 35392 Giessen, Germany
11University of Giessen and Marburg Lung Center (UGMLC); German Center for Lung Research (DZL), 35392 Giessen, Germany
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D von der Beck
1Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
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M Koch
1Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
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I Shalashova
1Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
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O Klymenko
1Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
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  • ORCID record for O Klymenko
L Fink
2Institute of Pathology, UEGP, 35578 Wetzlar, Germany
11University of Giessen and Marburg Lung Center (UGMLC); German Center for Lung Research (DZL), 35392 Giessen, Germany
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H Witt
3Department of Pediatrics, Technical University Munich, 85354 Freising, Germany
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H Hackstein
4Department of Clinical Immunology and Transfusion Medicine, 35392 Giessen, Germany
11University of Giessen and Marburg Lung Center (UGMLC); German Center for Lung Research (DZL), 35392 Giessen, Germany
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E El Agha
1Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
10Cardio-Pulmonary Institute (CPI), 35392 Giessen, Germany
11University of Giessen and Marburg Lung Center (UGMLC); German Center for Lung Research (DZL), 35392 Giessen, Germany
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S Bellusci
1Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
9Excellence Cluster Cardio-Pulmonary System (ECCPS), 35392 Giessen, Germany
10Cardio-Pulmonary Institute (CPI), 35392 Giessen, Germany
11University of Giessen and Marburg Lung Center (UGMLC); German Center for Lung Research (DZL), 35392 Giessen, Germany
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W Klepetko
5Department of Thoracic Surgery, Vienna General Hospital, 1090 Vienna, Austria
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M Königshoff
6Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Center Munich, Ludwig Maximilians University Munich; 81377 Munich, Germany
14Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, United States
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O Eickelberg
6Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Center Munich, Ludwig Maximilians University Munich; 81377 Munich, Germany
13Division of Respiratory Sciences and Critical Care Medicine, University of Colorado, United States
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T Braun
7Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
9Excellence Cluster Cardio-Pulmonary System (ECCPS), 35392 Giessen, Germany
10Cardio-Pulmonary Institute (CPI), 35392 Giessen, Germany
11University of Giessen and Marburg Lung Center (UGMLC); German Center for Lung Research (DZL), 35392 Giessen, Germany
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W Seeger
1Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
7Max-Planck-Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
9Excellence Cluster Cardio-Pulmonary System (ECCPS), 35392 Giessen, Germany
10Cardio-Pulmonary Institute (CPI), 35392 Giessen, Germany
11University of Giessen and Marburg Lung Center (UGMLC); German Center for Lung Research (DZL), 35392 Giessen, Germany
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C Ruppert
1Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
9Excellence Cluster Cardio-Pulmonary System (ECCPS), 35392 Giessen, Germany
11University of Giessen and Marburg Lung Center (UGMLC); German Center for Lung Research (DZL), 35392 Giessen, Germany
12European IPF Registry / Biobank, 35392 Giessen, Germany
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A Guenther
1Department of Internal Medicine, Justus-Liebig-University Giessen, 35392 Giessen, Germany
8Lung Clinic Waldhof-Elgershausen, 35753 Greifenstein, Germany
9Excellence Cluster Cardio-Pulmonary System (ECCPS), 35392 Giessen, Germany
10Cardio-Pulmonary Institute (CPI), 35392 Giessen, Germany
11University of Giessen and Marburg Lung Center (UGMLC); German Center for Lung Research (DZL), 35392 Giessen, Germany
12European IPF Registry / Biobank, 35392 Giessen, Germany
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  • For correspondence: Andreas.guenther@innere.med.uni-giessen.de
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Abstract

Alveolar epithelial cell type II (AEC2) injury underlies idiopathic pulmonary fibrosis (IPF). Here we show increased Notch1 signaling in AEC2s in human IPF and IPF models, causing enhanced proliferation and de-differentiation of AEC2s. As a result, we observed defective surfactant protein (SP)-B/C processing, elevated alveolar surface tension, repetitive alveolar collapse and development of lung fibrosis. Similar changes were encountered upon pharmacological inhibition of SP-B/C processing in vivo by pepstatin A. Inhibition of Notch signaling in cultured human IPF precision cut lung slices improved surfactant processing capacity of AEC2s and reversed fibrosis. Notch1 therefore offers as novel therapeutic target.

One sentence summary Notch1 inhibition restores alveolar epithelial differentiation and surface tension and reverses matrix deposition in lung fibrosis

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Posted March 23, 2019.
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Restored alveolar epithelial differentiation and reversed human lung fibrosis upon Notch inhibition
RM Wasnick, M Korfei, K Piskulak, I Henneke, J Wilhelm, P Mahavadi, D von der Beck, M Koch, I Shalashova, O Klymenko, L Fink, H Witt, H Hackstein, E El Agha, S Bellusci, W Klepetko, M Königshoff, O Eickelberg, T Braun, W Seeger, C Ruppert, A Guenther
bioRxiv 580498; doi: https://doi.org/10.1101/580498
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Restored alveolar epithelial differentiation and reversed human lung fibrosis upon Notch inhibition
RM Wasnick, M Korfei, K Piskulak, I Henneke, J Wilhelm, P Mahavadi, D von der Beck, M Koch, I Shalashova, O Klymenko, L Fink, H Witt, H Hackstein, E El Agha, S Bellusci, W Klepetko, M Königshoff, O Eickelberg, T Braun, W Seeger, C Ruppert, A Guenther
bioRxiv 580498; doi: https://doi.org/10.1101/580498

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