TGF-β1 induces human alveolar epithelial to mesenchymal cell transition (EMT)

Kasai, Hidenori; Allen, J. T.; Mason, Roger M.; Kamimura, Takashi; Zhang, Zhi

doi:10.1186/1465-9921-6-56

Cited by 664 publications

(612 citation statements)

References 52 publications

(65 reference statements)

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“…It is involved in a variety of normal physiological as well as pathological processes such as cancer progression and renal fibrosis (16,17). Recent evidence suggests a potential role for EMT in the pathogenesis of pulmonary fibrosis (14,15,(41)(42)(43). MFT is a similar process and has been described as a major factor in the development of peritoneal fibrosis (18).…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 Induces Progressive Pleural Scarring and Subpleural Fibrosis

Decologne

Kolb

Margetts

et al. 2007

The Journal of Immunology

116

119

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Pleural fibrosis is a misunderstood disorder which can cause severe restrictive lung disease with high morbidity and even mortality. The condition can develop in response to a large variety of diseases and tissue injury, among them infectious disease, asbestos, drugs, and radiation therapy. There is no efficient treatment to reverse established pleural fibrosis. TGF-β1 is suspected, even if not proven, as a key cytokine in this process. In this study, we used adenoviral gene transfer of TGF-β1 to the pleural mesothelium in rats. We show that local and transient TGF-β1 overexpression induces homogenous, prolonged, and progressive pleural fibrosis without pleurodesis, associated with severe impairment of pulmonary function. We further demonstrate that pleural fibrosis can expand into the lung parenchyma from the visceral layer, but not into the muscle from the parietal layer. We provide evidence that matrix accumulation and fibrosis within the parenchyma evolved through a process involving “mesothelial-fibroblastoid transformation” and suggest that the pleural mesothelial cell may be an important player involved in the development of the subpleural distribution pattern known to be a hallmark of pulmonary fibrosis. This new model of pleural fibrosis will allow us to better understand the mechanisms of progressive fibrogenesis, and to explore novel antifibrotic therapies in the pleural cavity.

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Section: Discussionmentioning

confidence: 99%

TGF-β1 Induces Progressive Pleural Scarring and Subpleural Fibrosis

Decologne

Kolb

Margetts

et al. 2007

The Journal of Immunology

116

119

View full text Add to dashboard Cite

show abstract

“…Our results indicated that TGF-β1 protein overexpression is closely associated with lung cancer progression and metastasis. As we all know, TGF-β1 is one of growth factors that can regulate extracellular matrix composition and induces epithelial-to-mesenchymal transition (EMT) in alveolar epithelial cell (Kasai et al, 2005). During the EMT process, carcinoma cells lose cell-cell adherence junctions and transfer to fibroblast-like morphology, and become motile and invasive.…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 Protein Expression in Non-Small Cell Lung Cancers is Correlated with Prognosis

Huang¹,

Liu²,

Qi³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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To investigate the expression intensity and prognostic significance of TGF-β1 protein in non-small cell lung cancer (NSCLC), immunohistochemistry was carried out in 194 cases of NSCLC and 24 cases of normal lung tissues by SP methods. The PU (positive unit) value was used to assess the TGF-β1 protein expression in systematically selected fields under the microscope with Leica Q500MC image analysis. We found that the TGF-β1 PU value was nearly two-fold higher in NSCLC than in normal lung tissues (p=0.000), being associated with TNM stages (p=0.000) and lymph node metastases (p=0.000), but not to patient age, gender, smoking history, tumor differentiation, histological subtype and tumor location (P>0.05). Univariate analysis indicated that patients with high TGF-β1 protein expression and lymph node metastases demonstrated a poor prognosis (both p=0.000, ). Multivariate analysis showed that TGF-β1 protein expression (RR = 2.565, p=0.002) and lymph node metastases (RR=1.874, p= 0.030) were also independent prognostic factors. Thus, TGF-β1 protein expression may be correlated to oncogenesis and serve as an independent prognostic biomarker for NSCLC.

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“…11 However, recently, it was shown that lung epithelial cells undergo epithelial-mesenchymal transition (EMT) to become myofibroblasts after treatment with TGF-b 1 in vitro. 12,13 The EMT of lung epithelial cells also seems to be induced in the lungs of pulmonary fibrosis patients and bleomycin-treated animals. 12,14 Furthermore, inhibition of EMT by knockout of the integrin-a3 gene has been shown to suppress bleomycininduced pulmonary fibrosis in mice.…”

mentioning

confidence: 99%

Induction of EMT-like phenotypes by an active metabolite of leflunomide and its contribution to pulmonary fibrosis

et al. 2010

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Drug-induced interstitial lung disease (ILD), particularly pulmonary fibrosis, is a serious clinical concern and myofibroblasts have been suggested to have a major role, with it recently being revealed that some of these myofibroblasts are derived from lung epithelial cells through epithelial-mesenchymal transition (EMT). In this study, we examined the EMT-inducing abilities of drugs known to induce ILD clinically. EMT-like phenotypes were induced by A771726, an active metabolite of leflunomide having an inhibitory effect on dihydroorotate dehydrogenase (DHODH). Smad-interacting protein 1 (a transcription factor regulating EMT) and the Notch-signaling pathway but not transforming growth factor-b was shown to be involved in A771726-induced EMT-like phenotypes. When the cultures were supplemented with exogenous uridine, the A771726-induced EMT-like phenotypes and activation of the Notch-signaling pathway disappeared. Similarly, an A771726 analog without inhibitory activity on DHODH produced no induction, suggesting that this process is mediated through the inhibition of DHODH. In vivo, administration of leflunomide stimulated bleomycin-induced EMT-like phenomenon in pulmonary tissue, and exacerbated bleomycin-induced pulmonary fibrosis, both of which were suppressed by coadministration of uridine. Taken together, these findings suggest that leflunomide-dependent exacerbation of bleomycin-induced pulmonary fibrosis is mediated by stimulation of EMT of lung epithelial cells, providing the first evidence that drug-induced pulmonary fibrosis involves EMT of these cells.

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TGF-β1 induces human alveolar epithelial to mesenchymal cell transition (EMT)

Cited by 664 publications

References 52 publications

TGF-β1 Induces Progressive Pleural Scarring and Subpleural Fibrosis

TGF-β1 Induces Progressive Pleural Scarring and Subpleural Fibrosis

TGF-β1 Protein Expression in Non-Small Cell Lung Cancers is Correlated with Prognosis

Induction of EMT-like phenotypes by an active metabolite of leflunomide and its contribution to pulmonary fibrosis

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