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WNT1-inducible signaling protein–1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis
Melanie Königshoff, … , Andreas Günther, Oliver Eickelberg
Melanie Königshoff, … , Andreas Günther, Oliver Eickelberg
Published March 16, 2009
Citation Information: J Clin Invest. 2009;119(4):772-787. https://doi.org/10.1172/JCI33950.
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Research Article Pulmonology Article has an altmetric score of 1

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

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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/β-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.

Authors

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

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Figure 4

Activation of WNT/β-catenin signaling in vivo during experimental lung fibrosis.

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Activation of WNT/β-catenin signaling in vivo during experimental lung f...
TOPGAL reporter mice were treated orotracheally with WNT3A or bleomycin, as described in detail in Methods. Supplemental Figure 3 depicts the treatment scheme. (A) X-gal staining of β-gal activity in lungs from WNT3A- and vehicle-treated mice (top row) or bleomycin- and saline-treated mice (bottom row). Pictures are representative of at least 2 independent experiments using at least 4 different lung tissues for each condition. (B) X-gal, SPC, and clara cell–specific protein (CCSP) protein expression in serial whole-lung sections from bleomycin-treated TOPGAL reporter mouse was assessed by immunohistochemistry. (C) Primary ATII cells were stimulated with WNT3A (100 ng/ml), and the mRNA levels of Ctgf, Wisp1, and Ccnd1 were analyzed by qRT-PCR (n = 4 for each) at the indicated time points and plotted as log-fold increase (ΔΔCt) of mRNA levels in WNT-stimulated versus unstimulated cells. Results are presented as mean ± SEM; *P < 0.05, **P < 0.02.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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