Restored alveolar epithelial differentiation and reversed human lung fibrosis upon Notch inhibition
Year: 2019
Type: preprint
Abstract: Alveolar epithelial cell type II (AEC2) injury underlies idiopathic pulmonary fibrosis (IPF). Here we show increased Notch1 signaling in AEC2s in human IPF and IPF models, causing enhanced proliferation and de-differentiation of AEC2s. As a result, we observed defective surfactant protein (SP)-B/C processing, elevated alveolar surface tension, repetitive alveolar collapse and development of lung fibrosis. Similar changes were encountered upon pharmacological inhibition of SP-B/C processing in vivo by pepstatin A. Inhibition of Notch signaling in cultured human IPF precision cut lung slices improved surfactant processing capacity of AEC2s and reversed fibrosis. Notch1 therefore offers as novel therapeutic target. One sentence summary Notch1 inhibition restores alveolar epithelial differentiation and surface tension and reverses matrix deposition in lung fibrosis
DOI: 10.1101/580498
Authors: RM Wasnick, M Korfei, K Piskulak, I Henneke, J Wilhelm, P Mahavadi, D von der Beck, M Koch, I Shalashova, O Klymenko, L Fink, H Witt, H Hackstein, E El Agha, S Bellusci, W Klepetko, M Königshoff, O Eickelberg, T Braun, W Seeger, C Ruppert, A Guenther
Institutions: Justus-Liebig-Universität Gießen, German Center for Lung Research, Universities of Giessen and Marburg Lung Center, Cardio-Pulmonary Institute, Technical University of Munich, Vienna General Hospital, Helmholtz Munich, University of Colorado Anschutz, Ludwig-Maximilians-Universität München, University of Colorado Denver, Max Planck Institute for Heart and Lung Research
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2921969598