Cited by 558Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisPulmonary Hypertension Research and TreatmentsTransplantation: Methods and Outcomes

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WNT1-inducible signaling protein–1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis

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Königshoff, Melanie, Kramer, Monika, Balsara, Nisha, Wilhelm, Jochen, Amarie, Oana Veronica, Jahn, Andreas, Rose, Frank, Fink, Ludger, Seeger, Werner, Schaefer, Liliana, Günther, Andreas, Eickelberg, Oliver·2009·Journal of Clinical Investigation

DOI 10.1172/jci33950PMC PMC2662540

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Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by distorted lung architecture and loss of respiratory function. Enhanced (myo)fibroblast activation, ECM deposition, and alveolar epithelial type II (ATII) cell dysfunction contribute to IPF pathogenesis. However, the molecular pathways linking ATII cell dysfunction with the development of fibrosis are poorly understood. Here, we demonstrate, in a mouse model of pulmonary fibrosis, increased proliferation and altered expression of components of the WNT/beta-catenin signaling pathway in ATII cells. Further analysis revealed that expression of WNT1-inducible signaling protein-1 (WISP1), which is encoded by a WNT target gene, was increased in ATII cells in both a mouse model of pulmonary fibrosis and patients with IPF. Treatment of mouse primary ATII cells with recombinant WISP1 led to increased proliferation and epithelial-mesenchymal transition (EMT), while treatment of mouse and human lung fibroblasts with recombinant WISP1 enhanced deposition of ECM components. In the mouse model of pulmonary fibrosis, neutralizing mAbs specific for WISP1 reduced the expression of genes characteristic of fibrosis and reversed the expression of genes associated with EMT. More importantly, these changes in gene expression were associated with marked attenuation of lung fibrosis, including decreased collagen deposition and improved lung function and survival. Our study thus identifies WISP1 as a key regulator of ATII cell hyperplasia and plasticity as well as a potential therapeutic target for attenuation of pulmonary fibrosis.

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Authors: Königshoff, M., Kramer, M., Balsara, N., Wilhelm, J., Amarie, O. V., Jahn, A., Rose, F., Fink, L., Seeger, W., Schaefer, L., Günther, A., & Eickelberg, O.
Affiliations: Justus-Liebig-Universität Gießen (DE)
Philipps University of Marburg (DE)
Goethe University Frankfurt (DE)
Helmholtz Munich (DE)
Corresponding author: Eickelberg, Oliver
ORCID: Wilhelm, Jochen
Amarie, Oana Veronica
Seeger, Werner
Schaefer, Liliana
Günther, Andreas
Eickelberg, Oliver
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2009-03-16
Volume: 119
Issue: 4
Pages: 772-87
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci33950
PMC: PMC2662540
OpenAlex: W2157101382
Cited by: 558
References: 72
Citations by year: 2026: 11 · 2025: 19 · 2024: 29 · 2023: 22 · 2022: 25 · 2021: 27 · 2020: 36 · 2019: 26 · 2018: 44 · 2017: 41 · 2016: 53 · 2015: 42 · 2014: 33 · 2013: 42 · 2012: 40
FWCI: 30.40
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Max Planck Institute for Plasma Physics (submittedVersion)
Site cant be reached (submittedVersion)
Funders: Alexander von Humboldt-Stiftung
Deutsche Forschungsgemeinschaft
Helmholtz Zentrum München
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
Keywords: WISP1, idiopathic pulmonary fibrosis, alveolar type II cells, Wnt/β-catenin signaling, epithelial-mesenchymal transition, extracellular matrix deposition, myofibroblast activation, collagen deposition, pulmonary fibrosis, therapeutic target, neutralizing antibodies
MeSH terms: Adult, Animals, Bleomycin, Disease Models, Animal, Epithelial Cells, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Models, Biological, Proto-Oncogene Proteins, Pulmonary Alveoli, Pulmonary Fibrosis, Recombinant Proteins, Oncogene Proteins, Up-Regulation, Intracellular Signaling Peptides and Proteins, Cell Proliferation, Wnt Proteins, beta Catenin, Mice, Idiopathic Pulmonary Fibrosis, CCN Intercellular Signaling Proteins

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WNT1-inducible signaling protein–1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis

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