Type II alveolar epithelial cells and interstitial fibroblasts express connective tissue growth factor in IPF

Pan, Lingai; Yamauchi, Kohei; Uzuki, Miwa; Nakanishi, Tōru; Takigawa, Masaharu; Inoue, Hiroshi; Sawai, Takashi

doi:10.1183/09031936.01.00074101

Cited by 183 publications

(112 citation statements)

References 28 publications

(14 reference statements)

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“…However, CTGF is consistently overexpressed in fibrotic lesions in patients with SSc and in those with other connective tissue diseases, affecting organs including the dermis, liver, kidney, heart, and lung (6,7). Elevated CTGF expression also correlates with, and contributes to, expression of ␣-smooth muscle actin (␣-SMA) and the myofibroblast phenotype in, for example, repair and development of connective tissue (8,9).…”

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confidence: 99%

Pivotal role of connective tissue growth factor in lung fibrosis: MAPK‐dependent transcriptional activation of type I collagen

Ponticos

Holmes

et al. 2009

Arthritis & Rheumatism

213

151

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Objective. Connective tissue growth factor (CTGF; CCN2) is overexpressed in systemic sclerosis (SSc) and has been hypothesized to be a key mediator of the pulmonary fibrosis frequently observed in this disease. CTGF is induced by transforming growth factor ␤ (TGF␤) and is a mediator of some profibrotic effects of TGF␤ in vitro. This study was undertaken to investigate the role of CTGF in enhanced expression of type I collagen in bleomycin-induced lung fibrosis, and to delineate the mechanisms of action underlying the effects of CTGF on Col1a2 (collagen gene type I ␣2) in this mouse model and in human pulmonary fibroblasts.Methods. Transgenic mice that were carrying luciferase and ␤-galactosidase reporter genes driven by the Col1a2 enhancer/promoter and the CTGF promoter, respectively, were injected with bleomycin to induce lung fibrosis (or saline as control), and the extracted pulmonary fibroblasts were incubated with CTGF blocking agents. In vitro, transient transfection, promoter/ reporter constructs, and electrophoretic mobility shift assays were used to determine the mechanisms of action of CTGF in pulmonary fibroblasts.Results. In the mouse lung tissue, CTGF expression and promoter activity peaked 1 week after bleomycin challenge, whereas type I collagen expression and Col1a2 promoter activity peaked 2 weeks postchallenge. Fibroblasts isolated from the mouse lungs 14 days after bleomycin treatment retained a profibrotic expression pattern, characterized by greatly elevated levels of type I collagen and CTGF protein and increased promoter activity. In vitro, inhibition of CTGF by specific small interfering RNA and neutralizing antibodies reduced the collagen protein expression and Col1a2 promoter activity. Moreover, in vivo, anti-CTGF antibodies applied after bleomycin challenge significantly reduced the Col1a2 promoter activity by ϳ25%. The enhanced Col1a2 promoter activity in fibroblasts from bleomycintreated lungs was partly dependent on Smad signaling, whereas CTGF acted on the Col1a2 promoter by a mechanism that was independent of the Smad binding site, but was, instead, dependent on the ERK-1/2 and JNK MAPK pathways. The CTGF effect was mapped to the proximal promoter region surrounding the inverted CCAAT box, possibly involving CREB and c-Jun. In human lung fibroblasts, the human COL1A2 promoter responded in a similar manner, and the mechanisms of action also involved ERK-1/2 and JNK signaling.Conclusion. Our results clearly define a direct profibrotic effect of CTGF and demonstrate its contribution to lung fibrosis through transcriptional activation

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confidence: 99%

Pivotal role of connective tissue growth factor in lung fibrosis: MAPK‐dependent transcriptional activation of type I collagen

Ponticos

Holmes

et al. 2009

Arthritis & Rheumatism

213

151

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“…In this disease, alveolar epithelial cells are elongated with a modification in the expression of cytokeratins. In addition, these cells are able to secrete pro-fibrotic factors, such as transforming growth factor (TGF)-b, connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), endothelin-1 and tumour necrosis factor (TNF)-a, and respond to these factors by modifying their morphology and differentiating into fibroblasts [16][17][18][19][20][21][22]. Studies in vitro in alveolar cell lines from rats (RLE-6TN), mice (AT2) and humans (A549) have demonstrated the occurrence of EMT in these cells in response to TGF-b [15,23,24].…”

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confidence: 99%

Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype

Pain

Bermúdez

Lacoste

et al. 2014

European Respiratory Review

171

128

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Airway remodelling is a critical feature of chronic bronchial diseases, characterised by aberrant repair of the epithelium and accumulation of fibroblasts, which contribute to extracellular matrix (ECM) deposition resulting in fixed bronchial obstruction. Recently, epithelial-mesenchymal transition (EMT) has been identified as a new source of fibroblasts that could contribute to the remodelling of the airways. This phenomenon consists of the loss of the epithelial phenotype by bronchial epithelial cells and the acquisition of a mesenchymal phenotype. These cells are then able to migrate and secrete ECM molecules. Herein, we review the different types of EMT. We will then focus on the signalling pathways that are involved, such as transforming growth factor-b and Wnt, as well as the more recently described Sonic Hedgehog pathway. Finally, we will highlight the implication of EMT in airway remodelling in specific chronic bronchial pathologies, such as asthma, chronic obstructive pulmonary disease and bronchiolitis obliterans following lung transplantation. Despite the limitations of in vitro models, future studies of EMT in vivo are warranted to shed new light on the pathomechanisms of bronchial obstruction. @ERSpublications Epithelial-mesenchymal transition in chronic bronchial remodelling diseases

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“…6 CCN2/CTGF is considered to be a marker of fibroblastic mesenchymal cells and is increased in cells undergoing epithelial to mesenchymal transition (EMT) in development, and in fibrosis. [7][8][9] The observation of elevated CCN2/CTGF levels in the epithelium of phenytoin gingival overgrowth lesions combined with the histopathology of all gingival overgrowth lesions has led us to test the hypothesis that EMT can contribute to human gingival overgrowth and fibrosis.…”

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Epithelial to Mesenchymal Transition in Gingival Overgrowth

Sume

Kantarcı

Lee

et al. 2010

The American Journal of Pathology

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Epithelial to mesenchymal transition (EMT) occurs normally in development. In pathology, EMT drives cancer and fibrosis. Medication with phenytoin, nifedipine, and cyclosporine-A often causes gingival overgrowth. Based partly on the histopathology of gingival overgrowth, the present study investigates the hypothesis that EMT could contribute to its development. We found that phenytoin-induced human gingival overgrowth tissues, the most fibrotic drug-induced variety, contain diminished epithelial E-cadherin expression, whereas fibroblast-specific protein-1 (FSP-1) and ␣v␤6 integrin levels are up-regulated. In connective tissue stroma, fibronectin and alternatively spliced fibronectin extra type III domain A (FN-ED-A) levels are increased in overgrowth lesions. Transforming growth factor (TGF)-␤1 treatment of primary human gingival epithelial cells cultured in transwell plates resulted in inhibited barrier function as determined by reduced electrical resistance, paracellular permeability assays, and cell surface E-cadherin expression. Moreover , TGF-␤1 altered the expression of other markers of EMT determined at the mRNA and protein levels: E-cadherin decreased, whereas SLUG, fibronectin, matrix metalloproteinase (MMP)2, MMP9, and MMP13 increased. Nifedipine-and cyclosporine A-induced gingival overgrowth tissues similarly contain diminished E-cadherin and elevated levels of FSP-1 and fibronectin, but normal levels of ␣v␤6 integrin. In summary, data in vitro support that human gingival epithelial cells undergo functional and gene expression changes consistent with EMT in response to TGF-␤1, and in vivo studies show that important EMT markers occur in clinical gingival overgrowth tissues. These findings support the hypothesis that EMT likely occurs in drug-induced gingival overgrowth.

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Type II alveolar epithelial cells and interstitial fibroblasts express connective tissue growth factor in IPF

Cited by 183 publications

References 28 publications

Pivotal role of connective tissue growth factor in lung fibrosis: MAPK‐dependent transcriptional activation of type I collagen

Pivotal role of connective tissue growth factor in lung fibrosis: MAPK‐dependent transcriptional activation of type I collagen

Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype

Epithelial to Mesenchymal Transition in Gingival Overgrowth

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