Table 1

Overview of molecular targets and applied tools/compounds to modify WNT signalling, which have been investigated in chronic lung diseases

TargetTools/compoundsDiseaseSummary of studyReferences
 WNT-1CCSP-driven WNT-1 overexpression (in vivo)Asthma
  • WNT-1 overexpression attenuated AHR, eosinophilia and number of mucus producing cells.

  • Reduced dendritic cell-mediated activation of T cells.

 WNT-5ARecombinant protein (in vitro)IPF/fibrosis
  • Enhances ECM deposition by lung fibroblasts in vitro.

  • Protects lung fibroblasts against oxidative stress-induced apoptosis.

Recombinant protein (in vitro)Physiological conditions
  • Facilitates β-catenin/p300 interaction in transdifferentiating primary rat alveolar type-II cells.

Surfactant protein C (SPC)-driven WNT-5A overexpression, recombinant protein, neutralising antibodies (in vitro and in vivo)COPD
  • Lung specific overexpression aggravates elastase-induced emphysema in vivo.

  • Attenuation of β-catenin-driven wound healing by alveolar epithelial cells.

  • In vivo inhibition of WNT-5A attenuated tissue destruction, improved lung function and restoration of alveolar epithelial cell markers expression in two animal models of COPD.

 LRP5LRP5−/− mice and siRNA (in vitro and in vivo)IPF/fibrosis
  • LRP5−/− mice are protected against bleomycin-induced lung fibrosis.

  • Delayed progression of asbestos-induced lung fibrosis in mice lacking LRP5.

 FZD4FzM1, FZD4 siRNA and overexpression (in vitro)COPD
  • FZD4 is expressed in alveolar epithelial cells and is reduced in COPD.

  • Inhibition of FZD4 by FzM1 decreased (WNT-3A-driven) β-catenin signalling in alveolar epithelial cells, whereas overexpression of FZD4 has the opposite effect.

  • FZD4 regulates wound healing and repair by the alveolar epithelium by facilitating cell proliferation, cell migration and ATII-to-ATI cell transdifferentiation.

 FZD8FZD8−/− mice and siRNA (in vitro and in vivo)IPF/fibrosis
  • FZD8−/− mice are partially protected against bleomycin-induced lung fibrosis.FZD8 siRNA attenuates TGF-β-induced ECM deposition by human lung fibroblasts.

  • Reduced cigarette smoke-induced inflammation in FZD8−/− mice compared with Wild type (WT) mice.

  • Association between SNP in FZD8 and chronic mucus hypersecretion in cohort of smokers.

  • Involvement of receptor in cytokine secretion by human lung fibroblasts.

Intercellular proteins
 FAM13AFAM13A−/− mice (in vivo)COPD
  • FAM13A is a COPD susceptibility gene.

  • Increased expression of FAM13A facilitates β-catenin degradation thereby contributing to emphysema development in two murine models of COPD.

 GSK-3βLiCl (in vitro)IPF/fibrosis/COPD
  • Pharmacological inhibition of GSK-3β enhances TGF-β-induced EMT

LiCl (in vivo)COPD
  • Inhibition of GSK-3β enhanced β-catenin in alveolar epithelial cells in vivo.

  • LiCl prevents the development and progression of elastase-induced emphysema.

SB216763 (in vivo)COPD
  • Inhibition of GSK-3β prevented right ventricle hypertrophy and small airway remodelling in a guinea pig model of LPS-induced COPD.

CT99021 or LiCl (ex vivo)COPD
  • GSK-3β inhibition in 3D-LTCs: increased alveolar epithelial cell marker expression, decreased MMP12 expression, and altered elastin remodelling.

Tankyrases XAV939 (in vivo and in vitro)IPF/fibrosis
  • Reduced β-catenin activation due to Axin stabilisation.

  • XAV939 attenuates bleomycin-induced lung fibrosis.

  • Inhibition of TKNS reduces fibroblast proliferation and myofibroblast differentiation.

β-catenin siRNA (in vivo)Asthma
  • siRNA against β-catenin resulted in reduced inflammation and airway remodelling in a murine model of OVA-induced asthma.

β-catenin interaction
 β-catenin/TCF ICAT (in vitro)Physiological conditions
  • Ectopic expression of Inhibitor of β-catenin and TCF (ICAT) impairs murine ATII-to-ATI cell transdifferentiation.

 β-catenin/TCF PKF115–584 (in vitro)Physiological conditions
  • Inhibition of β-catenin/TCF interaction by PKF115–584 impairs murine ATII-to-ATI cell transdifferentiation.

Physiological conditions
  • PKF115–584 prevents TGF-β-induced ECM deposition by human airway smooth muscle cells.

Physiological conditions
  • PKF115–584 decreases contractile force generation by airway smooth muscle.

Physiological conditions
  • Disruption of β-catenin/TCF interaction decreases ECM deposition by lung fibroblasts and prevents myofibroblast differentiation.

 β-catenin/CBP ICG-001 (in vitro and in vivo)Asthma
  • Reduced airway smooth muscle remodelling and ECM expression in a murine model of OVA-induced asthma in isolated smooth muscle cells.

ICG-001 (in vivo)IPF
  • Selective inhibition of the β-catenin/CBP interaction by the ICG-001 led to reversal of established bleomycin-induced pulmonary fibrosis and improved epithelial cell integrity.

 β-catenin/p300 IQ-1 (in vitro)Physiological conditions
  • Disruption of the β-catenin/p300 interaction interferes with rat ATII-to-ATI cell transdifferentiation.

  • IQ-1 partially stabilises SPC (ATII cell marker) expression, whereas the small molecule attenuates aquaporin5 (ATI cell marker) expression.

WNT target gene
 WISP1WISP1 neutralising antibodies (in vitro and in vivo)IPF
  • WISP1 is upregulated in murine model of bleomycin-induced fibrosis.

  • Neutralising mAbs specific for WISP1 reduced the expression of genes characteristic of fibrosis and reversed the expression of genes associated with EMT.

  • Inhibition of WISP1 attenuates pathological changes in experimental lung fibrosis in vivo.

  • Inhibition of WISP1 by neutralising antibodies results in less airway remodelling in a rat model of allergic asthma.

  • 3D-LTCs, three-dimensional lung tissue cultures; AHR, airway hyper-responsiveness; ATI (or II), alveolar epithelial type I (or II) cells; CBP, cAMP response element-binding protein binding protein; CCSP, Clara cell secretory protein; ECM, extracellular matrix; EMT, epithelial-to-mesenchymal transition; FZD, Frizzled receptor; GSK-3, glycogen synthase kinase-3; ICAT, inhibitor of β-catenin and TCF; IPF, idiopathic pulmonary fibrosis; LRP5−/−, mice lacking lipoprotein receptor-related protein 5; OVA, ovalbumin; SNP, single nucleotide polymorphism; TCF, T cell factor; WISP1, WNT1-inducible signalling protein-1.