Table 1

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

Target	Tools/compounds	Disease	Summary of study	References
Ligands
WNT-1	CCSP-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.	89
WNT-5A	Recombinant protein (in vitro)	IPF/fibrosis	▸ Enhances ECM deposition by lung fibroblasts in vitro. ▸ Protects lung fibroblasts against oxidative stress-induced apoptosis.	74
	Recombinant protein (in vitro)	Physiological conditions	▸ Facilitates β-catenin/p300 interaction in transdifferentiating primary rat alveolar type-II cells.	69
	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.	110
Receptors
LRP5	LRP5^−/− 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.	44
FZD4	FzM1, 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.	112
FZD8	FZD8^−/− 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.	71
		COPD	▸ 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.	123
Intercellular proteins
FAM13A	FAM13A^−/− 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.	111
GSK-3β	LiCl (in vitro)	IPF/fibrosis/COPD	▸ Pharmacological inhibition of GSK-3β enhances TGF-β-induced EMT	63
	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.	109
	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.	125
	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.	115
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.	45
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.	90
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.	48
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.	50
		Physiological conditions	▸ PKF115–584 prevents TGF-β-induced ECM deposition by human airway smooth muscle cells.	95
		Physiological conditions	▸ PKF115–584 decreases contractile force generation by airway smooth muscle.	97
		Physiological conditions	▸ Disruption of β-catenin/TCF interaction decreases ECM deposition by lung fibroblasts and prevents myofibroblast differentiation.	96
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.	94
	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.	42
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.	69
WNT target gene
WISP1	WISP1 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.	35
		Asthma	▸ Inhibition of WISP1 by neutralising antibodies results in less airway remodelling in a rat model of allergic asthma.	93

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.