Blockade of the Wnt/.BETA.-Catenin Pathway Attenuates Bleomycin-Induced Pulmonary Fibrosis

Kim, Tae Hyung; Kim, Sang‐Heon; Seo, Jae Hwa; Chung, Hae-Kyung; Kwak, Hyun Jung; Lee, Sangkyung; Yoon, Ho Joo; Shin, Dong Ho; Park, Sung Soo

doi:10.1620/tjem.223.45

Cited by 111 publications

(89 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Increased nuclear staining of b-catenin in bronchiolar lung epithelium and Type II alveolar epithelial cells from human IPF lung biopsies has been reported (4,5), and consistent with these results, a microarray analysis showed increases in genes associated with the Wnt/b-catenin pathway in IPF (6). Furthermore, various studies in a murine model of pulmonary fibrosis showed that b-catenin is activated in lung epithelium, and the inhibition of the Wnt/b-catenin pathway can attenuate (7) or reverse pulmonary fibrosis (8).…”

supporting

confidence: 79%

“…However, recent studies also suggest a role of the Wnt/b-catenin signaling pathway in EMT (32). Activated Wnt/b-catenin signaling has been demonstrated in lung epithelial cells in IPF (4,5), and in experimental models of fibrosis, the Wnt/b-catenin pathway was shown to be up-regulated (7,8). However, the exact role of Wnt/b-catenin in fibrosis remains to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Induction of a Mesenchymal Expression Program in Lung Epithelial Cells by Wingless Protein (Wnt)/β-Catenin Requires the Presence of c-Jun N-Terminal Kinase–1 (JNK1)

Velden

Guala

Leggett

et al. 2012

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Recent studies suggest the importance of the transition of airway epithelial cells (EMT) in pulmonary fibrosis, and also indicate a role for Wingless protein (Wnt)/b-catenin signaling in idiopathic pulmonary fibrosis. We investigated the possible role of the Wnt signaling pathway in inducing EMT in lung epithelial cells, and sought to unravel the role of c-Jun-N-terminal-kinase-1 (JNK1). The exposure of C10 lung epithelial cells or primary mouse tracheal epithelial cells (MTECs) to Wnt3a resulted in increases in JNK phosphorylation and nuclear b-catenin content. Because the role of b-catenin as a transcriptional coactivator is well established, we investigated T-cell factor/lymphocyteenhancement factor (TCF/LEF) transcriptional activity in C10 lung epithelial cells after the activation of Wnt. TCF/LEF transcriptional activity was enhanced after the activation of Wnt, and this increase in TCF/LEF transcriptional activity was diminished after the small interfering (si)RNA-mediated ablation of JNK. The activation of the Wnt pathway by Wnt3a, or the expression of either wild-type or constitutively active b-catenin (S37A), led to the activation of an EMT transcriptome, manifested by the increased mRNA expression of CArG box-binding factor-A, fibroblast-specific protein (FSP)-1, a-smooth muscle actin (a-SMA), and vimentin, increases in the content of a-SMA and FSP1, and the concomitant loss of zona occludens-1. The siRNA-mediated ablation of b-catenin substantially decreased Wnt3a-induced EMT. The siRNA ablation of JNK1 largely abolished Wnt3a, b-catenin, and b-catenin S37a-induced EMT. In MTECs lacking Jnk1, Wnt3a-induced increases in nuclear b-catenin, EMT transcriptome, and the content of a-SMA or FSP1 were substantially diminished. These data show that the activation of the Wnt signaling pathway is capable of inducing an EMT program in lung epithelial cells through b-catenin, and that this process is controlled by JNK1.Keywords: lung; epithelium; Wnt3a; fibrosis; epithelial to mesenchymal transitionThe development of fibrosis represents an important feature of pulmonary remodeling, and the critical role of epithelial cells in fibrogenesis is emerging. Studies from our laboratory identified a critical role for c-Jun-N-terminal-kinase-1 (JNK1) in augmenting the profibrotic effects of TGF-b1, in association with the causation of a mesenchymal transition of airway epithelialcells (EMT) (1). EMT is an important process during embryonic development, tumor progression, and fibrotic tissue repair after injury (2). We recently demonstrated that JNK1-induced phosphorylation in the linker domain of SMAD3 enhanced its ability to induce an EMT transcriptome. Consequently, JNK1-dependent, TGF-b1-induced EMT was greatly diminished in epithelial cells expressing a variant of SMAD3 refractory to phosphorylation in the linker domain (3).Recent studies indicated a role of b-catenin signaling in the induction of EMT. Moreover, the Wingless protein (Wnt)/ b-catenin axis was recently implicated to play a role in the development of idio...

show abstract

supporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Induction of a Mesenchymal Expression Program in Lung Epithelial Cells by Wingless Protein (Wnt)/β-Catenin Requires the Presence of c-Jun N-Terminal Kinase–1 (JNK1)

Velden

Guala

Leggett

et al. 2012

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

show abstract

“…FAM13A also promotes the assembly of the PP2Ab/b-catenin complex leading to degradation of b-catenin. It is noteworthy that activation of b-catenin signaling contributes to airway (18) and alveolar (21,54) epithelial repair/regeneration after various injuries. Hence, we connect FAM13A, located in one of the most consistently associated COPD GWAS regions, with b-catenin signaling, a potentially important repair pathway that determines COPD development and/or progression.…”

Section: /2mentioning

confidence: 99%

A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin

Jiang¹,

Lao²,

Qiu³

et al. 2016

Am J Respir Crit Care Med

101

134

View full text Add to dashboard Cite

Rationale: A genetic locus within the FAM13A gene has been consistently associated with chronic obstructive pulmonary disease (COPD) in genome-wide association studies. However, the mechanisms by which FAM13A contributes to COPD susceptibility are unknown.Objectives: To determine the biologic function of FAM13A in human COPD and murine COPD models and discover the molecular mechanism by which FAM13A influences COPD susceptibility. ) were generated and exposed to cigarette smoke. The lung inflammatory response and airspace size were assessed in Fam13a 2/2 and Fam13a 1/1 littermate control mice. Cellular localization of FAM13A protein and mRNA levels of FAM13A in COPD lungs were assessed using immunofluorescence, Western blotting, and reverse transcriptase-polymerase chain reaction, respectively. Immunoprecipitation followed by mass spectrometry identified cellular proteins that interact with FAM13A to reveal insights on FAM13A's function. ) were resistant to chronic cigarette smoke-induced emphysema compared with Fam13a 1/1 mice. In vitro, FAM13A interacts with protein phosphatase 2A and recruits protein phosphatase 2A with glycogen synthase kinase 3b and b-catenin, inducing b-catenin degradation. Fam13a 2/2 mice were also resistant to elastase-induced emphysema, and this resistance was reversed by coadministration of a b-catenin inhibitor, suggesting that FAM13A could increase the susceptibility of mice to emphysema development by inhibiting b-catenin signaling. Moreover, human COPD lungs had decreased protein levels of b-catenin and increased protein levels of FAM13A. Conclusions:We show that FAM13A may influence COPD susceptibility by promoting b-catenin degradation.

show abstract

“…Furthermore, inhibition of Wnt signaling (using β-catenin siRNA) can attenuate bleomycin-induced pulmonary fibrosis in mice (Kim et al 2011). These observations, suggesting an important role for Wnt signaling in fibro- Fig.…”

Section: Discussionmentioning

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.

View full text Add to dashboard Cite

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.

show abstract

Blockade of the Wnt/.BETA.-Catenin Pathway Attenuates Bleomycin-Induced Pulmonary Fibrosis

Cited by 111 publications

References 47 publications

Induction of a Mesenchymal Expression Program in Lung Epithelial Cells by Wingless Protein (Wnt)/β-Catenin Requires the Presence of c-Jun N-Terminal Kinase–1 (JNK1)

Induction of a Mesenchymal Expression Program in Lung Epithelial Cells by Wingless Protein (Wnt)/β-Catenin Requires the Presence of c-Jun N-Terminal Kinase–1 (JNK1)

A Chronic Obstructive Pulmonary Disease Susceptibility Gene, FAM13A, Regulates Protein Stability of β-Catenin

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

Contact Info

Product

Resources

About