WNT7B in fibroblastic foci of idiopathic pulmonary fibrosis

Meuten, Travis; Hickey, Ariel; Franklin, Katherine; Grossi, Brian; Tobias, Jeremy R.; Newman, Donna; Jennings, Sydney; Correa, María T.; Sannes, Philip L.

doi:10.1186/1465-9921-13-62

Cited by 39 publications

(54 citation statements)

References 37 publications

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“…Although our findings argue against FGF2 specifically being required for bleomycininduced pulmonary fibrosis in mice, they do not argue against FGF signaling via any of the other 17 secreted FGF ligands. FGF9 expression, for example, is increased in areas of active fibrosis in IPF lungs, and is further enhanced by Tgfb1 and Wnt7B, which are coexpressed in these regions (48,49). Consistent with prior reports, we observed an increase in downstream FGF signaling in response to bleomycin (10).…”

Section: Fgf2 and Pulmonary Fibrosissupporting

confidence: 81%

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

Guzy

Stoilov

Elton³

et al. 2015

Am J Respir Cell Mol Biol

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The pathogenesis of pulmonary fibrosis involves lung epithelial injury and aberrant proliferation of fibroblasts, and results in progressive pulmonary scarring and declining lung function. In vitro, fibroblast growth factor (FGF) 2 promotes myofibroblast differentiation and proliferation in cooperation with the profibrotic growth factor, transforming growth factor-b1, but the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. The bleomycin model of lung injury and pulmonary fibrosis was applied to Fgf2 knockout (Fgf2 2/2) and littermate control mice. Weight loss, mortality, pulmonary fibrosis, and histology were analyzed after a single intranasal dose of bleomycin. Inflammation was evaluated in bronchoalveolar lavage (BAL) fluid, and epithelial barrier integrity was assessed by measuring BAL protein and Evans Blue dye permeability. Fgf2 is expressed in mouse and human lung epithelial and inflammatory cells, and, in response to bleomycin, Fgf2 2/2 mice have significantly increased mortality and weight loss. Analysis of BAL fluid and histology show that pulmonary fibrosis is unaltered, but Fgf2 2/2 mice fail to efficiently resolve inflammation, have increased BAL cellularity, and, importantly, deficient recovery of epithelial integrity. Fgf2 2/2 mice similarly have deficient recovery of club cell secretory protein 1 bronchial epithelium in response to naphthalene. We conclude that FGF2 is not required for bleomycin-induced pulmonary fibrosis, but rather is essential for epithelial repair and maintaining epithelial integrity after bleomycin-induced lung injury in mice. These data identify that FGF2 acts as a protective growth factor after lung epithelial injury, and call into question the role of FGF2 as a profibrotic growth factor in vivo.Keywords: fibroblast growth factor 2; bleomycin; pulmonary fibrosis; lung injury; alveolar epithelial repair Clinical RelevanceFibroblast growth factors (FGFs) and, in particular, FGF2, are implicated in the pathogenesis of pulmonary fibrosis and recovery from airway epithelial cell (AEC) injury; however, the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. In this study, we have found that mice lacking FGF2 do not show altered levels of fibrosis in response to bleomycin, indicating that FGF2 is dispensable for the generation of bleomycin-induced pulmonary fibrosis. In addition, we show that FGF2 knockout mice have increased mortality and weight loss in response to bleomycin, accompanied by deficient recovery of mature alveolar epithelium and epithelial barrier function. These findings suggest that FGF2 is required for lung epithelial recovery, that pharmacological inhibition of FGF signaling could impair the response to lung injury, and that FGF2 administration or augmentation may have therapeutic benefit for lung injury.Lung alveolar epithelial cell (AEC) injury can be caused by a variety of insults, including infection, trauma, aspiration, and sepsis. Chronic AEC injury of unknown origin is central to ...

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Section: Fgf2 and Pulmonary Fibrosissupporting

confidence: 81%

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

Guzy

Stoilov

Elton³

et al. 2015

Am J Respir Cell Mol Biol

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“…Wnt7B is known to be important during early lung development as a signaling glycopeptide that directs proliferation of adjacent epithelium and mesenchymal cells (Rajagopal et al 2008) and controls the growth of vasculature (Shu et al 2002). This has led to the suggestion that Wnt7B may be reactivated to significantly impact the progression of IPF in the adult lung (Morrisey 2003;Meuten et al 2012).…”

Section: Discussionmentioning

confidence: 99%

“…TGF-β is probably best known for its regulatory influences on fibrogenesis in IPF (Chilosi et al 2003;Fernandez and Eickelberg 2012) by fostering the growth of myofibroblasts and the expansion of fibrillar collagen and various components of the ECM, which, in many cases, is cooperatively controlled by Wnt signaling (Broekelmann et al 1991;Scotton and Chambers 2007;Salazar, Lankford, and Brody 2009). Wnt7B gene expression has been reported to be upregulated in IPF lungs (Konigshoff et al 2008) and found to be localized in tissue sections within distinct sites that include cells and the ECM within FF of IPF lungs (Meuten et al 2012). Wnt7B is known to be important during early lung development as a signaling glycopeptide that directs proliferation of adjacent epithelium and mesenchymal cells (Rajagopal et al 2008) and controls the growth of vasculature (Shu et al 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Both Wnt7B and TGF-β1 are present in or near fibroblastic foci (Khalil et al, 1991;Meuten et al, 2012) and could be expected to modulate Wnt5A expression. To model in vivo conditions and potentially enhance Wnt5A expression, some hLF, IPFF, and hASMC cells were transduced (in suspension for 1 hr with occasional re-suspension before plating) with CMV-GFP or CMV-LacZ (control) or CMV-Wnt7B (for Wnt7B overexpression) adenoviruses at 50 MOI (Multiplicity of Infection) for 24-30 hr before overnight quiescence in 0.1% FBS medium and treatment with vehicle (4 mM HCl/1 mg/ml BSA) or recombinant human TGF-β1 (240-B; R&D Systems, Minneapolis, MN) at 5-10 ng/ml for 24-36 hr before termination.…”

Section: Adenoviral Transduction For Overexpression and Silencing Anmentioning

confidence: 99%

“…The study was approved by the North Carolina State University Institutional Review Board. Paraffin blocks were sectioned and stained with hematoxylin and eosin (H&E) and examined by a board-certified pathologist to independently confirm/reclassify initial clinical diagnoses (Meuten et al 2012).…”

Section: Immunostainingmentioning

confidence: 99%

See 2 more Smart Citations

Expression of WNT5A in Idiopathic Pulmonary Fibrosis and Its Control by TGF-β and WNT7B in Human Lung Fibroblasts

Newman

Sills

Hanrahan

et al. 2015

J Histochem Cytochem.

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The wingless (Wnt) family of signaling ligands contributes significantly to lung development and is highly expressed in patients with usual interstitial pneumonia (UIP). We sought to define the cellular distribution of Wnt5A in the lung tissue of patients with idiopathic pulmonary fibrosis (IPF) and the signaling ligands that control its expression in human lung fibroblasts and IPF myofibroblasts. Tissue sections from 40 patients diagnosed with IPF or UIP were probed for the immunolocalization of Wnt5A. Further, isolated lung fibroblasts from normal or IPF human lungs, adenovirally transduced for the overexpression or silencing of Wnt7B or treated with TGF-β1 or its inhibitor, were analyzed for Wnt5A protein expression. Wnt5A was expressed in IPF lungs by airway and alveolar epithelium, smooth muscle cells, endothelium, and myofibroblasts of fibroblastic foci and throughout the interstitium. Forced overexpression of Wnt7B with or without TGF-β1 treatment significantly increased Wnt5A protein expression in normal human smooth muscle cells and fibroblasts but not in IPF myofibroblasts where Wnt5A was already highly expressed. The results demonstrate a wide distribution of Wnt5A expression in cells of the IPF lung and reveal that it is significantly increased by Wnt7B and TGF-β1, which, in combination, could represent key signaling pathways that modulate the pathogenesis of IPF.

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CGRP induces myofibroblast differentiation and the production of extracellular matrix in MRC5s via autocrine and paracrine signalings

Kayalar

Öztay

2022

J Biochem & Molecular Tox

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There are contradictory views on which calcitonin gene-related peptide (CGRP) causes pulmonary fibrosis. Fibrotic potency of CGRP was tested and compared to that of transforming growth factor-β (TGF-β). Myofibroblast differentiation, cell proliferation, and activations of TGF-β and Wnt pathways were examined for 24, 48, and 72 h in A549 and MRC5 cell lines stimulated with CGRP and TGF-β. CGRPinduced cell proliferation in MRC5s early on while cell proliferation in A549 occurred progressively. CGRP promoted fibroblast-myofibroblast differentiation by inducing the transcription of ACTA2, COL1A1, SMAD2/3, and SMAD4 genes, the production of collagen, fibronectin, α-smooth muscle actin, and activation of TGF-β signaling starting from 24 h. Additionally, TGF-β signaling induced by CGRP decreased the DKK1 level and activated the Wnt signaling in MRC5s. After CGRP stimulation, Wnt7a levels were increased from 24 to 72 h, while Wnt5a levels were elevated at 72 h in MRC5s. CGRP did not induce epithelial-mesenchymal transition in A549s, unlike TGF-β. A comparison of fibrotic potency of CGRP and TGF-β showed that TGF-β is a powerful profibrotic molecule and induces earlier myofibroblast differentiation. Even so, CGRP promotes myofibroblast differentiation and extracellular matrix production by inducing Smad-dependent-TGF-β and Wnt signalings via autocrine and paracrine signalings in MRC5s.

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WNT7B in fibroblastic foci of idiopathic pulmonary fibrosis

Cited by 39 publications

References 37 publications

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

Expression of WNT5A in Idiopathic Pulmonary Fibrosis and Its Control by TGF-β and WNT7B in Human Lung Fibroblasts

CGRP induces myofibroblast differentiation and the production of extracellular matrix in MRC5s via autocrine and paracrine signalings

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