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

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

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 5

Increased WISP1 expression in ATII cells in vitro and in vivo in experimental lung fibrosis.

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Increased WISP1 expression in ATII cells in vitro and in vivo in IPF. (A...
(A) Time-course analysis of CCN family member gene expression was performed using qRT-PCR of lung homogenates harvested 7, 14, or 21 days after administration of bleomycin. Respective mRNA levels were plotted as log-fold change (ΔΔCt) of mRNA levels in bleomycin- versus time-matched saline-treated mice (n = 4) and are presented as mean ± SEM. (B) WISP1 protein expression was assessed using immunohistochemical staining of whole-lung sections of bleomycin- or saline-treated mice 14 days after application (upper panels) and Western blot analysis in total protein lysates (lower panels). Recombinant mouse WISP1 protein served as a positive control; β-actin served as a loading control. Data are representative of at least 2 independent experiments using 6 (Saline) or 5 (Bleo) different lung tissues each. (C) The mRNA levels of all CCN family members were determined by qRT-PCR in primary ATII cells (black bars, n = 6) or primary mouse fibroblasts (mFb; white bars, n = 4) isolated from the lungs of saline- or bleomycin-treated mice 14 days after administration. Results are plotted as log-fold change (ΔΔCt) of mRNA levels in bleomycin-derived versus saline-derived cells and are presented as mean ± SEM. (D) WISP1 protein expression was assessed using double immunostaining for ECAD (green) and WISP1 (red) of primary ATII cells from saline- or bleomycin-treated mice, respectively (original magnification, ×40). Nuclei were visualized by DAPI staining (inset; original magnification, ×40). Data are representative of at least 3 independent experiments.*P < 0.05, **P < 0.02.