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 2

Increased mRNA expression of Wisp1 and WNT signaling components in ATII cells isolated from bleomycin-treated mice.

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Increased mRNA expression of Wisp1 and WNT signaling components in ATII ...
(A) ATII cell gene expression profiles were analyzed by whole genome expression analysis using RNA from freshly isolated ATII cells from saline- or bleomycin-treated mouse lungs 14 days after administration. Red and green indicate increased and decreased gene expression levels, respectively, in ATII cells isolated from bleomycin- versus saline-treated mice. Columns represent individual samples, including dye-swap experiments. Selected genes are represented in rows. Detailed description of the whole genome expression analysis is given in the Supplemental Data. (B) Confirmation of microarray results was performed for selected genes in freshly isolated ATII cells (n = 6), as well as in ATII cells 72 hours after isolation (n = 3) by qRT-PCR, as indicated. The following genes were analyzed: secreted frizzled-related protein 1 (Sfrp1), inhibin beta A (Inhba), found in inflammatory zone 1 (Fizz1), secreted phosphoprotein 1 (Spp1), Wisp1, cadherin 16 (Cdh16), and potassium voltage-gated channel subfamily E member 2 (Kcne2). Results are presented as mean ± SEM; **P < 0.02 for all bars, compared with ATII cells isolated from saline-treated mice. (C and D) The mRNA levels of the WNT target gene Mmp7, the WNT ligands Wnt1, Wnt2, Wnt3a, Wnt7b, and Wnt10b (C), the receptors frizzled 1 (Fzd1), Fzd2, and Fzd4, and the intracellular signal transducers Ctnnb1, Gsk3b, and Tcf4 (D) were assessed in ATII cells isolated from bleomycin- and saline-treated mice (n = 6 each) by qRT-PCR. Results are presented as mean ± SEM. *P < 0.05, **P < 0.02.