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 10

WISP1 neutralization in vivo leads to the attenuation of lung fibrosis.

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WISP1 neutralization in vivo leads to the attenuation of lung fibrosis. ...
(A) Mice were subjected to saline or bleomycin instillation, as described above, and treated either with neutralizing α-WISP1 antibodies or preimmune serum (IgG control) by orotracheal application as described in detail in Methods. Lungs were processed 14 days after bleomycin application for immunohistochemical analysis and stained for type I collagen. (B) Total collagen content in lung homogenates was quantified using the Sircol collagen assay. Results are derived from whole lungs harvested 14 days after saline, bleomycin, bleomycin plus preimmune serum (IgG control), or bleomycin plus neutralizing α-WISP1 antibody instillation by orotracheal application (n = 5 each). Results are presented as mean ± SEM; **P < 0.02, #P < 0.02 versus Bleo + IgG treatment. (C) Indicated lung sections were used for immunohistochemical analysis and stained with α-SMA. Pictures are representative of at least 2 independent experiments using at least 4 different lung tissues for each condition.