Wnt Signaling and Pulmonary Fibrosis

Morrisey, Edward E.

doi:10.1016/s0002-9440(10)64271-x

Cited by 106 publications

(97 citation statements)

References 54 publications

(40 reference statements)

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“…1H). The calcium-binding protein S100A4, (i.e., FSP-1), has been suggested to be a fibroblast-specific marker and hallmark of EMT, which may represent a common pathway in diseases marked by airway remodeling (9,24) and reduction of FSP-1 expression in fibroblasts may be associated with mesenchymal-epithelial transition. We conclude that bleomycin activates Wnt/β-catenin signaling in the lung, and that ICG-001 effectively decreases the bleomycin-induced aberrant Wnt/β-catenin signaling in both the epithelium and in fibroblasts.…”

Section: Icg-001 Inhibits Activation Of Wnt/β-catenin Signaling In Thmentioning

confidence: 99%

“…The Wnt/β-catenin pathway initiates a signaling cascade critical in normal development of multiple organ systems, including the brain, intestines, skin, and lung (9). The hallmark of this pathway is that it activates the transcriptional role of the multifunctional protein β-catenin.…”

mentioning

confidence: 99%

“…In this regard, analysis of β-catenin expression in IPF lungs revealed an increase in the number of cells expressing nuclear (activated) β-catenin in association with up-regulation of Wnt target genes (16). It was suggested that up-regulation of Wnt signaling may promote proliferation of AT2 cells and inhibit their ability to differentiate into AT1 cells (9), impairing the repair process and, given the importance of Wnt/β-catenin to EMT in other settings, may also induce injured AT2 cells to undergo EMT. Consistent with these results, microarray analysis revealed up-regulation of genes related to the Wnt/β-catenin pathway (17), and in a more detailed analysis that included primary AT2 cells derived from IPF patients, components of the Wnt signaling pathway and its downstream targets were increased at both gene and protein levels (16).…”

mentioning

confidence: 99%

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Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis

Henderson

Emil

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

422

328

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Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia is a ravaging condition of progressive lung scarring and destruction. Anti-inflammatory therapies including corticosteroids have limited efficacy in this ultimately fatal disorder. An important unmet need is to identify new agents that interact with key molecular pathways involved in the pathogenesis of pulmonary fibrosis to prevent progression or reverse fibrosis in these patients. Because aberrant activation of the Wnt/β-catenin signaling cascade occurs in lungs of patients with IPF, we have targeted this pathway for intervention in pulmonary fibrosis using ICG-001, a small molecule that specifically inhibits T-cell factor/β-catenin transcription in a cyclic AMP response-element binding protein binding protein (CBP)-dependent fashion. ICG-001 selectively blocks the β-catenin/CBP interaction without interfering with the β-catenin/p300 interaction. We report here that ICG-001 (5 mg/kg per day) significantly inhibits β-catenin signaling and attenuates bleomycin-induced lung fibrosis in mice, while concurrently preserving the epithelium. Administration of ICG-001 concurrent with bleomycin prevents fibrosis, and late administration is able to reverse established fibrosis and significantly improve survival. Because no effective treatment for IPF exists, selective inhibition of Wnt/β-catenin-dependent transcription suggests a potential unique therapeutic approach for pulmonary fibrosis.

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Section: Icg-001 Inhibits Activation Of Wnt/β-catenin Signaling In Thmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis

Henderson

Emil

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

422

328

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“…The Wnt/β-catenin signaling pathway plays important roles in cellular proliferation and differentiation (Morrisey 2003), and has been implicated in the pathogenesis of vari-ous fibrotic diseases, including lung fibrosis (Guo et al 2012). Wnt ligands are extracellular proteins that activate cell surface receptors, which in turn recruit β-catenin in the signal transduction pathway.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Potential of Umbilical Cord Mesenchymal Stem Cells for Inhibiting Myofibroblastic Differentiation of Irradiated Human Lung Fibroblasts

Zhang

Zhu

Zhang

et al. 2015

Tohoku J. Exp. Med.

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Radiation-induced lung injury (RILI) limits the benefits of radiotherapy in patients with lung cancer. Radiation-induced differentiation of lung fibroblasts to myofibroblasts plays a key role in RILI. Recent studies have shown that mesenchymal stem cells (MSCs) can protect against lung fibrosis and that Wnt/ β-catenin signaling is involved in fibrotic processes. In the present study, we explored the therapeutic potential of human umbilical cord MSCs (HUMSCs) for preventing radiation-induced differentiation of human lung fibroblasts (HLFs) to myofibroblasts. There are two advantages in the use of HUMSCs; namely, they are easily obtained and have low immunogenicity. Irradiated HLFs were co-cultured with HUMSCs. Expression of α-smooth muscle actin (α-SMA), a myofibroblast marker, was measured by Western blot analysis and immunohistochemistry. Irradiation (X-rays, 5 Gy) induced the differentiation of HLFs into myofibroblasts, which was inhibited by co-culture with HUMSCs. Irradiation also caused activation of the canonical Wnt/β-catenin signaling in HLFs, as judged by increased phosphorylation of glycogen synthase kinase 3β, nuclear accumulation of β-catenin, and elevated levels of Wnt-inducible signaling protein-1 (WISP-1) in the conditioned medium. However, co-culture with HUMSCs attenuated the radiation-induced activation of the Wnt/β-catenin signaling. We also measured the expression of FRAT1 that can enhance the Wnt/β-catenin signaling by stabilizing β-catenin. Co-culture with HUMSCs decreased FRAT1 protein levels in irradiated nHLFs. Thus, co-culture with HUMSCs attenuated the radiation-induced activation of Wnt/β-catenin signaling in HLFs, thereby inhibiting myofibroblastic differentiation of HLFs. Wnt/β-catenin signaling is a potential therapeutic target for limiting RILI in patients receiving radiotherapy for lung cancer.

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“…Wnt/β-catenin signaling is an early developmental pathway that plays an important role in airway and vascular smooth muscle cell development (8)(9)(10). Wnt signaling has been shown to be upregulated in the lungs of adult patients with idiopathic lung fibrosis and PH (11)(12)(13).…”

mentioning

confidence: 99%

Inhibition of LRP5/6-mediated Wnt/β-catenin signaling by Mesd attenuates hyperoxia-induced pulmonary hypertension in neonatal rats

et al. 2013

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Background: Hyperoxia-induced neonatal lung injury is associated with activation of Wnt/β-catenin signaling. Lowdensity lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are Wnt coreceptors that bind to Wnt ligands and mediate canonical Wnt/β-catenin signaling. We hypothesized that inhibition of LRP5/6 by their universal inhibitor, Mesd, would attenuate hyperoxia-induced lung injury. Methods: Newborn rat pups were randomly exposed to normoxia or hyperoxia at 90% FiO 2 and injected intraperitoneally with placebo or Mesd every other day for 14 d. On day 15, phosphorylation of LRP5/6 (pLRP5/6), expression of Wnt/ β-catenin target genes, cyclin D1 and Wnt-induced signaling protein-1 (WISP-1), right-ventricular systolic pressure (RVSP), right-ventricular hypertrophy (RVH), pulmonary vascular remodeling, alveolarization, and vascularization were measured. results: Hyperoxia exposure markedly induced pLRP5/6, cyclin D1, and WISP-1 expression in the lungs of placebo animals, but they were significantly attenuated by the administration of Mesd. Mesd also significantly attenuated hyperoxiainduced pulmonary hypertension (PH) and pulmonary vascular remodeling. However, there was no effect on alveolarization or vascularization after Mesd administration. conclusion: This study demonstrates that LRP5/6 mediates pulmonary vascular remodeling and PH in hyperoxia-induced neonatal lung injury, thereby suggesting a potential therapeutic target to alleviate PH in neonates with severe bronchopulmonary dysplasia.

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Wnt Signaling and Pulmonary Fibrosis

Cited by 106 publications

References 54 publications

Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis

Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis

Therapeutic Potential of Umbilical Cord Mesenchymal Stem Cells for Inhibiting Myofibroblastic Differentiation of Irradiated Human Lung Fibroblasts

Inhibition of LRP5/6-mediated Wnt/β-catenin signaling by Mesd attenuates hyperoxia-induced pulmonary hypertension in neonatal rats

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