Congenital Deletion of <i>Nedd4-2</i> in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice
Recent studies found that expression of NEDD4-2 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and that the conditional deletion of <i>Nedd4-2</i> in lung epithelial cells causes IPF-like disease in adult mice via multiple defects, including dysregulatio...
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/11/6146 |
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| author | Dominik H. W. Leitz Julia Duerr Surafel Mulugeta Ayça Seyhan Agircan Stefan Zimmermann Hiroshi Kawabe Alexander H. Dalpke Michael F. Beers Marcus A. Mall |
| author_facet | Dominik H. W. Leitz Julia Duerr Surafel Mulugeta Ayça Seyhan Agircan Stefan Zimmermann Hiroshi Kawabe Alexander H. Dalpke Michael F. Beers Marcus A. Mall |
| author_sort | Dominik H. W. Leitz |
| collection | DOAJ |
| description | Recent studies found that expression of NEDD4-2 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and that the conditional deletion of <i>Nedd4-2</i> in lung epithelial cells causes IPF-like disease in adult mice via multiple defects, including dysregulation of the epithelial Na<sup>+</sup> channel (ENaC), TGFβ signaling and the biosynthesis of surfactant protein-C proprotein (proSP-C). However, knowledge of the impact of congenital deletion of <i>Nedd4-2</i> on the lung phenotype remains limited. In this study, we therefore determined the effects of congenital deletion of <i>Nedd4-2</i> in the lung epithelial cells of neonatal doxycycline-induced triple transgenic <i>Nedd4-2<sup>fl/fl</sup>/CCSP-rtTA2<sup>S</sup>-M2/LC1</i> mice, with a focus on clinical phenotype, survival, lung morphology, inflammation markers in BAL, mucin expression, ENaC function and proSP-C trafficking. We found that the congenital deletion of <i>Nedd4-2</i> caused a rapidly progressive lung disease in neonatal mice that shares key features with interstitial lung diseases in children (chILD), including hypoxemia, growth failure, sterile pneumonitis, fibrotic lung remodeling and high mortality. The congenital deletion of <i>Nedd4-2</i> in lung epithelial cells caused increased expression of <i>Muc5b</i> and mucus plugging of distal airways, increased ENaC activity and proSP-C mistrafficking. This model of congenital deletion of <i>Nedd4-2</i> may support studies of the pathogenesis and preclinical development of therapies for chILD. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T10:38:53Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3c6b0915d4e245e79120f1761299b0e92023-11-21T23:06:10ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012211614610.3390/ijms22116146Congenital Deletion of <i>Nedd4-2</i> in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal MiceDominik H. W. Leitz0Julia Duerr1Surafel Mulugeta2Ayça Seyhan Agircan3Stefan Zimmermann4Hiroshi Kawabe5Alexander H. Dalpke6Michael F. Beers7Marcus A. Mall8Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyDepartment of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyDivision of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk Suite 216, Philadelphia, PA 19104, USATranslational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), Department of Translational Pulmonology, University of Heidelberg, Im Neuenheimer Feld 156, 69120 Heidelberg, GermanyDepartment of Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, 69120 Heidelberg, GermanyDepartment of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str. 3D, 37075 Goettingen, GermanyInstitute of Medical Microbiology and Virology, Medical Faculty, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, 01307 Dresden, GermanyDivision of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk Suite 216, Philadelphia, PA 19104, USADepartment of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyRecent studies found that expression of NEDD4-2 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and that the conditional deletion of <i>Nedd4-2</i> in lung epithelial cells causes IPF-like disease in adult mice via multiple defects, including dysregulation of the epithelial Na<sup>+</sup> channel (ENaC), TGFβ signaling and the biosynthesis of surfactant protein-C proprotein (proSP-C). However, knowledge of the impact of congenital deletion of <i>Nedd4-2</i> on the lung phenotype remains limited. In this study, we therefore determined the effects of congenital deletion of <i>Nedd4-2</i> in the lung epithelial cells of neonatal doxycycline-induced triple transgenic <i>Nedd4-2<sup>fl/fl</sup>/CCSP-rtTA2<sup>S</sup>-M2/LC1</i> mice, with a focus on clinical phenotype, survival, lung morphology, inflammation markers in BAL, mucin expression, ENaC function and proSP-C trafficking. We found that the congenital deletion of <i>Nedd4-2</i> caused a rapidly progressive lung disease in neonatal mice that shares key features with interstitial lung diseases in children (chILD), including hypoxemia, growth failure, sterile pneumonitis, fibrotic lung remodeling and high mortality. The congenital deletion of <i>Nedd4-2</i> in lung epithelial cells caused increased expression of <i>Muc5b</i> and mucus plugging of distal airways, increased ENaC activity and proSP-C mistrafficking. This model of congenital deletion of <i>Nedd4-2</i> may support studies of the pathogenesis and preclinical development of therapies for chILD.https://www.mdpi.com/1422-0067/22/11/6146Nedd4-2animal modelinterstitial lung diseasechILDENaCproSP-C |
| spellingShingle | Dominik H. W. Leitz Julia Duerr Surafel Mulugeta Ayça Seyhan Agircan Stefan Zimmermann Hiroshi Kawabe Alexander H. Dalpke Michael F. Beers Marcus A. Mall Congenital Deletion of <i>Nedd4-2</i> in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice International Journal of Molecular Sciences Nedd4-2 animal model interstitial lung disease chILD ENaC proSP-C |
| title | Congenital Deletion of <i>Nedd4-2</i> in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice |
| title_full | Congenital Deletion of <i>Nedd4-2</i> in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice |
| title_fullStr | Congenital Deletion of <i>Nedd4-2</i> in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice |
| title_full_unstemmed | Congenital Deletion of <i>Nedd4-2</i> in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice |
| title_short | Congenital Deletion of <i>Nedd4-2</i> in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice |
| title_sort | congenital deletion of i nedd4 2 i in lung epithelial cells causes progressive alveolitis and pulmonary fibrosis in neonatal mice |
| topic | Nedd4-2 animal model interstitial lung disease chILD ENaC proSP-C |
| url | https://www.mdpi.com/1422-0067/22/11/6146 |
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