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Wasnick, R.* ; Korfei, M.* ; Piskulak, K.* ; Henneke, I.* ; Wilhelm, J.* ; Mahavadi, P.* ; Dartsch, R.C.* ; von der Beck, D.* ; Koch, M.* ; Shalashova, I.* ; Weiss, A.R.* ; Klymenko, O.* ; Askevold, I.* ; Fink, L.* ; Witt, H.* ; Hackstein, H.* ; El Agha, E.* ; Bellusci, S.* ; Klepetko, W.* ; Königshoff, M. ; Eickelberg, O.* ; Schermuly, R.T.* ; Braun, T.* ; Seeger, W.* ; Ruppert, C.* ; Guenther, A.*

Notch1 induces defective epithelial surfactant processing and pulmonary fibrosis.

Am. J. Respir. Crit. Care Med. 207, 283-299 (2023)
DOI PMC
Rationale: Although type II alveolar epithelial cells (AEC2s) are chronically injured in idiopathic pulmonary fibrosis (IPF), they contribute to epithelial regeneration in IPF. Objectives: We hypothesized that Notch signaling may contribute to AEC2 proliferation, dedifferentiation characterized by loss of surfactant processing machinery, and lung fibrosis in IPF. Methods: We applied microarray analysis, kinome profiling, flow cytometry, immunofluorescence analysis, western blotting, quantitative PCR, and proliferation and surface activity analysis to study epithelial differentiation, proliferation, and matrix deposition in vitro (AEC2 lines, primary murine/human AEC2s), ex vivo (human IPF-derived precision-cut lung slices), and in vivo (bleomycin and pepstatin application, Notch1 [Notch receptor 1] intracellular domain overexpression). Measurements and Main Results: We document here extensive SP-B and -C (surfactant protein-B and -C) processing defects in IPF AEC2s, due to loss of Napsin A, resulting in increased intra-alveolar surface tension and alveolar collapse and induction of endoplasmic reticulum stress in AEC2s. In vivo pharmacological inhibition of Napsin A results in the development of AEC2 injury and overt lung fibrosis. We also demonstrate that Notch1 signaling is already activated early in IPF and determines AEC2 fate by inhibiting differentiation (reduced lamellar body compartment, reduced capacity to process hydrophobic SP) and by causing increased epithelial proliferation and development of lung fibrosis, putatively via altered JAK (Janus kinase)/Stat (signal transducer and activator of transcription) signaling in AEC2s. Conversely, inhibition of Notch signaling in IPF-derived precision-cut lung slices improved the surfactant processing capacity of AEC2s and reversed fibrosis. Conclusions: Notch1 is a central regulator of AEC2 fate in IPF. It induces alveolar epithelial proliferation and loss of Napsin A and of surfactant proprotein processing, and it contributes to fibroproliferation.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords interstitial lung disease; diffuse parenchymal lung disease; lung surfactant; epithelial regeneration; idiopathic pulmonary fibrosis; Alveolar Type-ii; C-based Surfactant; Signaling Controls; Lung Development; Stem-cells; Differentiation; Pneumonitis; Expression; Quantification; Regeneration
ISSN (print) / ISBN 1073-449X
e-ISSN 1535-4970
Journal American Journal of Respiratory and Critical Care Medicine
Quellenangaben Volume: 207, Issue: 3, Pages: 283-299 Article Number: , Supplement: ,
Publisher American Thoracic Society
Publishing Place 25 Broadway, 18 Fl, New York, Ny 10004 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Lung Repair and Regeneration (LRR)
Grants Lung Fibrosis Foundation Waldhof-Elgershausen
European Commission
German Ministry of Science and Education (German Center for Lung Research, DA DPLD Funds)