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 11

WISP1 inhibition in vivo leads to decreased profibrotic marker gene expression and increased survival in lung fibrosis.

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WISP1 inhibition in vivo leads to decreased profibrotic marker gene expr...
(A) Indicated lung sections were used for immunohistochemical analysis and stained with H&E. (B and C) mRNA levels of the profibrotic marker genes Col1a1, Spp1, Mmp7, Pai1, and Ctgf (B) and the EMT marker genes Tjp1, Cdh1, Ocln, Fsp1, Vim, and Acta2 (C) were analyzed by qRT-PCR (n = 5 each). Results are plotted as log-fold change (ΔΔCt) of mRNA levels in lung specimens 14 days after bleomycin instillation treated with neutralizing α-WISP1 antibodies, compared with lungs treated with preimmune serum (IgG control). Results are presented as mean ± SEM. See Supplemental Figure 9, A and B, for a comparison of all treatment groups. (D) Lung compliance measurements were obtained from mice instilled with saline, bleomycin, bleomycin plus IgG control, or bleomycin plus α-WISP1 antibody (n = 10 for each), 14 days after initial exposure to bleomycin. (E) The survival of mice subjected to neutralizing α-WISP1 or preimmune serum (IgG control) instillations (n = 18 for each) was monitored. Days of antibody instillations are indicated on the x axis. *P < 0.05, **P < 0.02; #P < 0.02 versus Bleo + IgG treatment.