Distinct Roles of Wnt/β-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Table 1

Wnt signaling involved in the pathogenesis of COPD and IPF.

Disease	Wnt signaling	Model	Function/mechanism	Ref.
COPD	Wnt/β-catenin and PKC signaling	HBEC cells	An interaction of Wnt/β-catenin and PKC signaling reduced nicotine-induced surfactant protein A (SPA) SPD: surfactant protein D (SPD) in HBEC cells	[49]
COPD	Wnt5B	BEAS-2B and PBEC cells	An exaggerated Wnt5B expression upon cigarette smoke exposure led to TGF-β/Smad3-dependent expression of genes related to airway remodeling in the bronchial epithelium of COPD patients	[50]
COPD	Wnt/β-catenin	3D cultures of murine and patient-derived lung tissue cultures (LTCs)	Enhanced Wnt/β-catenin signaling using GSK3β; inhibitor LiCl and CHIR 99021 attenuated; pathological features of COPD patient-derived 3D-LTCs	[51]
COPD	Wnt/β-catenin signaling	Human primary pulmonary fibroblasts derived from non-COPD individuals	Wnt/β-catenin signaling contributes to ECM; production and differentiation pulmonary; fibroblasts by pulmonary fibroblasts	[47]
COPD	Wnt3a/β-catenin; signaling pathway	HBEC cells	Wnt3a/β-catenin signaling promotes HBEC cells undergoing EMT upon nicotine stimulation in vitro	[52]
COPD	Noncanonical Wnt5B signaling	Human primary pulmonary fibroblasts; derived from COPD patients and; non-COPD individuals	Wnt5B induces IL-6 and CXCL8 secretion in pulmonary fibroblasts through FZD2 receptor and TAK1 signaling	[53]
COPD	Wnt/β-catenin signaling	HBEC cells, mouse lung tissues, and mouse models	Wnt/β-catenin has an essential role in airway; inflammation of COPD by PPARδ/p38 MAPK pathway,; a cigarette smoke reduced this signaling activation which; promotes inflammatory cytokine production in; airway epithelium	[54]
COPD	Wnt/β-catenin signaling	Murine emphysema models	A decreased Wnt/β-catenin signaling activity is involved in parenchymal tissue destruction and impaired repair capacity in lung of murine emphysema model	[14]
COPD	Wnt/β-catenin signaling	Human lung epithelial cell lines and PBEC cells	Wnt4 expression is downregulated in airway epithelial cells exposed to cigarette smoke extract (CSE), which in turn induces proinflammatory cytokine release of cells	[55]
COPD	FZD4, Wnt/β-catenin signaling	Lung tissues and primary AECII cells of COPD patients and smokers, mouse emphysema models	Reduced expression of FZD4 prevents Wnt/β-catenin-driven alveolar lung repair in COPD	[56]
COPD	Wnt5A	Elastase and CS-induced COPD murine models	An inhibition of Wnt5A-mediated noncanonical Wnt signaling leads the attenuation of lung tissue destruction, improvement of lung function, and restoration of expression of Wnt/β-catenin signaling target genes in the elastase and CS-induced COPD models	[46, 57]
COPD	Noncanonical Wnt signaling	FZD8-deficient mice, primary human; lung fibroblasts, and primary human; airway epithelial cells	FZD8 receptor is associated with chronic bronchitis; and is involved in cytokine secretion from human; pulmonary fibroblasts as well as acute CS-induced; inflammation in mice	[58]
IPF	Wnt/β-catenin; signaling and TGF-β	Pulmonary fibroblasts, bleomycin-induced pulmonary fibrosis murine model	An inhibition of Wnt/β-catenin signaling by targeting Dvl leads an effective alleviation of fibrotic lung diseases in mice.	[59]
IPF	Wnt/β-catenin, DKK1, DKK4	Human bronchial and alveolar epithelial cell lines/bronchoalveolar tissues	DKK1 and DKK4 proteins are expressed in human IPF; lung epithelia; Wnt/β-catenin-induced epithelial cell; proliferation can be regulated by DKK1 in a; dose-dependent fashion	[60]
IPF	Wnt/β-catenin; signaling pathway	C57BL/6N mice	Blockade of the Wnt/β-catenin signaling cascade; attenuates bleomycin-induced PF in mice	[61]
IPF	Wnt7B	Human lung tissue samples	Wnt7B is expressed at high concentrations in regions of active hyperplasia, metaplasia, and fibrotic change of lungs in IPF patients	[62]
IPF	Wnt10A	Beomycin-induced mouse PF model	Wnt10A activates TGF-β signaling, which plays an important role in the pathogenesis of IPF via TGF-β activation, suggesting it may be a sensitive predictor for the onset of human IPF	[63]
IPF	Wnt/β-catenin; signaling, Wnt5A/B	Human diagnostic biopsies/donated lungs	An interaction between the inhibition of β-catenin; signaling and activation of Wnt5A/B is correlated; with aberrant nonfibrotic parenchyma in IPF lungs	[9]
IPF	Wnt5A	IPF or UIP tissue sections	A wide distribution of Wnt5A is expressed in cells of IPF lung, which can be significantly induced by Wnt7B and TGF-β1	[64]
IPF	Wnt1inducible; signaling protein-1; (WISP1)	A mouse model of pulmonary fibrosis, AECII cells	WISP1 is a key regulator of AECII cell hyperplasia in pulmonary fibrosis of murine models	[48]
IPF	Wnt/β-catenin/CREB binding protein (CBP) signaling	Bleomycin-induced lung fibrosis in mice	ICG-001 is selective blockade for β-catenin/CBP, which; shows ability to prevent fibrosis when it is concurrent; with bleomycin and reverse established fibrosis and; significantly improve survival of bleomycin-induced; lung fibrosis mice	[65]
IPF	Wnt/β-catenin signaling	Bleomycin-induced lung fibrosis mice	Wnt coreceptor, LRP5, is a genetic driver of lung fibrosis in bleomycin-induced lung fibrosis mice, which can be served as a marker of disease progression and severity in patients with IPF	[66]
IPF	Wnt coreceptor LRP5	Primary murine AECTII cells	Revealed that the alveolar epithelium is a relevant; source of proinflammatory cytokines induced by; active Wnt/β-catenin in pulmonary fibrosis	[67]
IPF	Wnt/β-catenin signaling	A549 cell line and bleomycin-induced pulmonary fibrosis Sprague Dawley rat model	Wnt/beta-catenin signaling activates TGF-beta/Smad2/3; signaling for myofibroblast proliferation in vitro; and in vivo	[68]
IPF	Wnt/β-catenin signaling	Human lung biopsies from IPF patients and non-IPF individuals	Single cell RNA-Seq revealed aberrant canonical Wnt signaling activation in IPF	[69]
PF	Wnt/β-catenin signaling	Coculture of BM-MSCs and AECII cells, NIH/3T3 fibroblasts	Wnt/β-catenin signaling inhibitor XAV939 is able to promote the differentiation of BM-MSCs into an epithelium-like phenotype in the coculture system, which also shows a capacity to inhibit the proliferation and myofibroblast differentiation of NIH/3T3 fibroblasts	[61]
PF	Wnt/β-catenin signaling	MLE-12 cells	Regulatory T-cell- (Treg-) promoted EMT of MLE-12 cells is mediated by Wnt/β-catenin signaling	[70]
PF	Wnt/β-catenin signaling	Bleomycin-induced murine fibrotic lung tissue and primary AECII cells	An inhibition of Wnt/β-catenin signaling suppressed the aberrant expression of TGF-β1 and FGF2 in bleomycin-induced murine fibrotic lung tissues and primary AECII cells, suggesting Wnt/β-catenin pathway can be served as a potential therapeutic strategy for PF	[71]
PF	Wnt antagonists, SFRP1, and FRZB	Alveolar epithelial cell line, lung fibroblast cell line, and bleomycin-induced lung fibrosis murine model	SFRP1 counteracts the effect of TGF-β1in pulmonary cells in vitro, but loss of neither SFRP1 nor FRZB alters fibrotic outcomes in the lungs in mice	[72]
PF	Wnt/β-catenin signaling	BALB/c mice	An upregulation of β-catenin and elevation of TGF-β1 are associated with PTX-mediated transformation of pulmonary emphysema into pulmonary fibrosis under chronic a CS exposure	[73]
PF	Wnt/β-catenin signaling	HCl-induced acute lung injury SD rats	The aberrant activation of Wnt/β-catenin signaling induces the myofibroblast differentiation of engrafted MSCs in HCl-induced acute lung injury SD rats	[74]
PF	Wnt/β-catenin signaling	Primary lung microvascular endothelial cells, bleomycin-induced lung fibrosis mice	Repeated systemic administrations disrupt a normally fine-tuned balance in the Wnt signaling and induce reactive oxygen species (ROS) to cause DNA damage and fibrosis partially be affecting the endothelial niche	[75]
PF	LRP5, Wnt/β-catenin signaling	Bleomycin-induced lung fibrosis mice, LRP5-deficient mice	LRP5/β-catenin signaling controls alveolar macrophage differentiation and inhibits resolution of pulmonary fibrosis	[76]
PF	Wnt/β-catenin signaling	Human IMR-90 lung fibroblast cells	TGF-β1 can activate Wnt/β-catenin signaling pathway	[77]

3D-LTCs: three-dimensional lung tissue cultures; AEC II: alveolar epithelial cell type II; ASM: airway smooth muscle; APC: adenomatous polyposis coli; BALF: bronchoalveolar lavage fluid; BM-MSCs: bone marrow-derived mesenchymal stem cells; CBP: CREB-binding protein; COPD: chronic obstructive pulmonary disease; CS: cigarette smoke; CSE: cigarette smoke extract; CTGF: connective tissue growth factor; CXCL: chemokine (C-X-C motif) ligand; DAAM1: dishevelled associated activator of morphogenesis 1; DKK: Dickkopf; Dvl: disheveled; ECM: extracellular matrix; EMMPRIN: extracellular matrix metalloproteinase inducer; EMT: epithelial-mesenchymal transition; FEV1: forced expiratory volume in 1 second; FGF: fibroblast growth factor; FRZB: frizzled-related protein; FZD: frizzled; GSK: glycogen synthase kinase; HBECs: human bronchial epithelial cells; hBSMC: human bronchial smooth muscle cell; IL: interleukin; IPF: idiopathic pulmonary fibrosis; JNK: c-Jun N-terminal protein kinases; LRP: low-density lipoprotein-related receptor; MLE: mouse lung epithelial; MMP: matrix metalloproteinase; NFAT: nuclear factor of activated T-cells; NF-κB: nuclear factor-κB; NLK: nemo-like kinase; PBEC: primary bronchial epithelial cell; PBMC: peripheral blood mononuclear cell; PF: pulmonary fibrosis; PKC: protein kinase C; PSMCs: parabronchial smooth muscle cells; PTX: pentoxifylline; Ror: receptor tyrosine kinase-like orphan receptor; RYK: receptor-like tyrosine kinase; SD: Sprague Dawley; SFRP1: secreted frizzled-related protein-1; shRNA: short hairpin RNA; siRNA: small interfering RNA; SMA: smooth muscle actin; SPA: surfactant protein A; SPD: surfactant protein D; TAK1: transforming growth factor-β activated kinase-1; TCF/LEF1: T-cell factor/lymphoid enhancer factor 1; TGF-β: transforming growth factor-beta; TNFα: tumor necrosis factor α; Th2: helper 2 T-cells; UIP: usual interstitial pneumonia; WIF1: Wnt inhibitory factor 1; WISP1: Wnt1 inducible signaling pathway protein-1; Wnt: wingless-type MMTV integration site.