Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice

Julia Duerr (), Dominik H. W. Leitz, Magdalena Szczygiel, Dmytro Dvornikov, Simon G. Fraumann, Clemens Kreutz, Piotr K. Zadora, Ayça Seyhan Agircan, Philip Konietzke, Theresa A. Engelmann, Jan Hegermann, Surafel Mulugeta, Hiroshi Kawabe, Lars Knudsen, Matthias Ochs, Daniela Rotin, Thomas Muley, Michael Kreuter, Felix J. F. Herth, Mark O. Wielpütz, Michael F. Beers, Ursula Klingmüller and Marcus A. Mall ()
Additional contact information
Julia Duerr: University of Heidelberg, Im Neuenheimer Feld 156
Dominik H. W. Leitz: University of Heidelberg, Im Neuenheimer Feld 156
Magdalena Szczygiel: German Center for Lung Research (DZL), Im Neuenheimer Feld 156
Dmytro Dvornikov: German Center for Lung Research (DZL), Im Neuenheimer Feld 156
Simon G. Fraumann: University of Heidelberg, Im Neuenheimer Feld 156
Clemens Kreutz: University of Freiburg, Stefan-Meier-Straße 26
Piotr K. Zadora: German Center for Lung Research (DZL), Im Neuenheimer Feld 156
Ayça Seyhan Agircan: University of Heidelberg, Im Neuenheimer Feld 156
Philip Konietzke: German Center for Lung Research (DZL), Im Neuenheimer Feld 156
Theresa A. Engelmann: Hannover Medical School
Jan Hegermann: Hannover Medical School
Surafel Mulugeta: Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard
Hiroshi Kawabe: Max Planck Institute of Experimental Medicine
Lars Knudsen: Hannover Medical School
Matthias Ochs: Hannover Medical School
Daniela Rotin: 555 University Avenue
Thomas Muley: German Center for Lung Research (DZL), Im Neuenheimer Feld 156
Michael Kreuter: German Center for Lung Research (DZL), Im Neuenheimer Feld 156
Felix J. F. Herth: German Center for Lung Research (DZL), Im Neuenheimer Feld 156
Mark O. Wielpütz: German Center for Lung Research (DZL), Im Neuenheimer Feld 156
Michael F. Beers: Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard
Ursula Klingmüller: German Center for Lung Research (DZL), Im Neuenheimer Feld 156
Marcus A. Mall: University of Heidelberg, Im Neuenheimer Feld 156

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15743-6

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