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

Autor: Ayça Seyhan Agircan, Alexander H. Dalpke, Julia Duerr, Marcus A. Mall, Michael F. Beers, Surafel Mulugeta, Hiroshi Kawabe, Stefan Zimmermann, Dominik H. W. Leitz
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Epithelial sodium channel
Male
proSP-C
Pathology
Nedd4 Ubiquitin Protein Ligases
Pulmonary Fibrosis
Pathogenesis
Idiopathic pulmonary fibrosis
Mice
0302 clinical medicine
Pulmonary fibrosis
Nedd4-2
Biology (General)
Lung
Spectroscopy
Mice
Knockout
interstitial lung disease
Interstitial lung disease
General Medicine
respiratory system
Computer Science Applications
Chemistry
medicine.anatomical_structure
Female
medicine.symptom
Inflammation Mediators
medicine.medical_specialty
chILD
QH301-705.5
ENaC
Inflammation
macromolecular substances
Catalysis
Article
Inorganic Chemistry
03 medical and health sciences
medicine
Animals
Physical and Theoretical Chemistry
Molecular Biology
QD1-999
Pneumonitis
business.industry
animal model
Organic Chemistry
Epithelial Cells
medicine.disease
respiratory tract diseases
Mice
Inbred C57BL
Pulmonary Alveoli
030104 developmental biology
030228 respiratory system
Animals
Newborn
business
Zdroj: International Journal of Molecular Sciences
Volume 22
Issue 11
International Journal of Molecular Sciences, Vol 22, Iss 6146, p 6146 (2021)
ISSN: 1422-0067
DOI: 10.3390/ijms22116146
Popis: 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 Nedd4-2fl/fl/CCSP-rtTA2S-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.
Databáze: OpenAIRE
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