Congenital Deletion of Nedd4-2 in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice

International Journal of Molecular Sciences

卷:22

Stefan Zimmermann¹  Hiroshi Kawabe²  Dominik H. W. Leitz³  Marcus A. Mall³  Julia Duerr³  Surafel Mulugeta⁴  Michael F. Beers⁴  Alexander H. Dalpke⁵  Ayça Seyhan Agircan⁶ 

[1] Department of Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, 69120 Heidelberg, Germany;

[2] Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str. 3D, 37075 Goettingen, Germany;

[3] Department 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, Germany;

[4] Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, 3450 Hamilton Walk Suite 216, Philadelphia, PA 19104, USA;

[5] Institute of Medical Microbiology and Virology, Medical Faculty, University Hospital Carl Gustav Carus Dresden, Technische Universität Dresden, 01307 Dresden, Germany;

[6] Translational 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, Germany;

关键词: Nedd4-2;    animal model;    interstitial lung disease;    chILD;    ENaC;    proSP-C;   

DOI  :  10.3390/ijms22116146

来源: DOAJ

【 摘 要 】

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 Nedd4-2 in lung epithelial cells causes IPF-like disease in adult mice via multiple defects, including dysregulation of the epithelial Na⁺ channel (ENaC), TGFβ signaling and the biosynthesis of surfactant protein-C proprotein (proSP-C). However, knowledge of the impact of congenital deletion of Nedd4-2 on the lung phenotype remains limited. In this study, we therefore determined the effects of congenital deletion of Nedd4-2 in the lung epithelial cells of neonatal doxycycline-induced triple transgenic Nedd4-2^fl/fl/CCSP-rtTA2^S-M2/LC1 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 Nedd4-2 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 Nedd4-2 in lung epithelial cells caused increased expression of Muc5b and mucus plugging of distal airways, increased ENaC activity and proSP-C mistrafficking. This model of congenital deletion of Nedd4-2 may support studies of the pathogenesis and preclinical development of therapies for chILD.

【 授权许可】

Unknown