Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice
| Autor: | Dmytro Dvornikov, Jan Hegermann, Simon G. Fraumann, Daniela Rotin, Surafel Mulugeta, Felix Herth, Michael Kreuter, Julia Duerr, Hiroshi Kawabe, Magdalena Szczygiel, Ayça Seyhan Agircan, Ursula Klingmüller, Clemens Kreutz, Mark O. Wielpütz, Dominik Leitz, Matthias Ochs, Marcus A. Mall, Theresa A. Engelmann, Philip Konietzke, Piotr K. Zadora, Thomas Muley, Michael F. Beers, Lars Knudsen |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Proteomics
0301 basic medicine Pathology Ubiquitylation Biopsy Nedd4 Ubiquitin Protein Ligases General Physics and Astronomy Pathogenesis Mice Idiopathic pulmonary fibrosis 0302 clinical medicine Fibrosis Pulmonary fibrosis lcsh:Science Lung Mice Knockout Multidisciplinary Interstitial lung disease Pirfenidone Middle Aged respiratory system Mucin-5B humanities 3. Good health medicine.anatomical_structure 030220 oncology & carcinogenesis medicine.drug Adult medicine.medical_specialty Pyridones Science Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences medicine Animals Humans Epithelial Sodium Channels Aged NEDD4L Respiratory tract diseases business.industry Ubiquitination Epithelial Cells General Chemistry medicine.disease Idiopathic Pulmonary Fibrosis respiratory tract diseases Disease Models Animal 030104 developmental biology lcsh:Q business |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-18 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by patchy scarring of the distal lung with limited therapeutic options and poor prognosis. Here, we show that conditional deletion of the ubiquitin ligase Nedd4-2 (Nedd4l) in lung epithelial cells in adult mice produces chronic lung disease sharing key features with IPF including progressive fibrosis and bronchiolization with increased expression of Muc5b in peripheral airways, honeycombing and characteristic alterations in the lung proteome. NEDD4-2 is implicated in the regulation of the epithelial Na+ channel critical for proper airway surface hydration and mucus clearance and the regulation of TGFβ signaling, which promotes fibrotic remodeling. Our data support a role of mucociliary dysfunction and aberrant epithelial pro-fibrotic response in the multifactorial disease pathogenesis. Further, treatment with the anti-fibrotic drug pirfenidone reduced pulmonary fibrosis in this model. This model may therefore aid studies of the pathogenesis and therapy of IPF. Idiopathic pulmonary fibrosis (IPF) is a devastating disease with poor prognosis. Here, the authors show that deficiency of the E3 ubiqutin-protein ligase Nedd4-2 in airway epithelial cells causes IPF-like disease in adult mice. This model may aid studies of the pathogenesis and therapy of IPF. |
| Databáze: | OpenAIRE |
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