Resveratrol inhibits transforming growth factor-β–induced proliferation and differentiation of ex vivo human lung fibroblasts into myofibroblasts through ERK/Akt inhibition and PTEN restoration

Fagone, Evelina; Conte, Enrico; Gili, Elisa; Fruciano, Mary; Pistorio, Maria Provvidenza; Furno, Debora Lo; Giuffrida, Rosario; Crimi, Nunzio; Vancheri, Carlo

doi:10.3109/01902148.2010.524722

Cited by 50 publications

(47 citation statements)

References 34 publications

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“…The tumor suppressor phosphatase and tensin homolog (PTEN) acts to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate (PIP3), resulting in inhibition of the PI3K-Akt pathway. Low expression of PTEN and activation of the PI3K-Akt pathway have been found in lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) [10], [11]; thus, we inferred that LPS may promote lung fibroblast proliferation by down-regulating PTEN expression and activating the PI3K-Akt pathway in the early stages of ALI/ARDS.…”

Section: Introductionmentioning

confidence: 86%

Lipopolysaccharide Induces Lung Fibroblast Proliferation through Toll-Like Receptor 4 Signaling and the Phosphoinositide3-Kinase-Akt Pathway

Gao

Deng

et al. 2012

PLoS ONE

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Pulmonary fibrosis is characterized by lung fibroblast proliferation and collagen secretion. In lipopolysaccharide (LPS)-induced acute lung injury (ALI), aberrant proliferation of lung fibroblasts is initiated in early disease stages, but the underlying mechanism remains unknown. In this study, we knocked down Toll-like receptor 4 (TLR4) expression in cultured mouse lung fibroblasts using TLR4-siRNA-lentivirus in order to investigate the effects of LPS challenge on lung fibroblast proliferation, phosphoinositide3-kinase (PI3K)-Akt pathway activation, and phosphatase and tensin homolog (PTEN) expression. Lung fibroblast proliferation, detected by BrdU assay, was unaffected by 1 mug/mL LPS challenge up to 24 hours, but at 72 hours, cell proliferation increased significantly. This proliferation was inhibited by siRNA-mediated TLR4 knockdown or treatment with the PI3K inhibitor, Ly294002. In addition, siRNA-mediated knockdown of TLR4 inhibited the LPS-induced up-regulation of TLR4, down-regulation of PTEN, and activation of the PI3K-Akt pathway (overexpression of phospho-Akt) at 72 hours, as detected by real-time PCR and Western blot analysis. Treatment with the PTEN inhibitor, bpV(phen), led to activation of the PI3K-Akt pathway. Neither the baseline expression nor LPS-induced down-regulation of PTEN in lung fibroblasts was influenced by PI3K activation state. PTEN inhibition was sufficient to exert the LPS effect on lung fibroblast proliferation, and PI3K-Akt pathway inhibition could reverse this process. Collectively, these results indicate that LPS can promote lung fibroblast proliferation via a TLR4 signaling mechanism that involves PTEN expression down-regulation and PI3K-Akt pathway activation. Moreover, PI3K-Akt pathway activation is a downstream effect of PTEN inhibition and plays a critical role in lung fibroblast proliferation. This mechanism could contribute to, and possibly accelerate, pulmonary fibrosis in the early stages of ALI/ARDS.

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Section: Introductionmentioning

confidence: 86%

Lipopolysaccharide Induces Lung Fibroblast Proliferation through Toll-Like Receptor 4 Signaling and the Phosphoinositide3-Kinase-Akt Pathway

Gao

Deng

et al. 2012

PLoS ONE

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“…For instance, bleomycin-induced pulmonary fibrosis is accompanied by enhanced expression of TGF␤1, collagen 1, and ␣SMA (Zhang et al, 1996). TGF␤ induces the proliferation and differentiation of ex vivo human lung fibroblasts into myofibroblasts through extracellular signal-regulated kinase/Akt inhibition and Pten restoration, whereas Res inhibits this process (Fagone et al, 2011). PQ increased TGF␤1 production, but pretreatment with Res for 16 h could prevent PQ-induced TGF␤1 expression.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Inhibits Paraquat-Induced Oxidative Stress and Fibrogenic Response by Activating the Nuclear Factor Erythroid 2-Related Factor 2 Pathway

Wang²,

Szklarz³

et al. 2012

J Pharmacol Exp Ther

117

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Nuclear factor erythroid 2-related factor 2 (Nrf2) is an antioxidant-activated transcription factor that recently emerged as a critical regulator of cellular defense against oxidative and inflammatory lesions. Resveratrol (Res) is a natural phytoalexin that exhibits multiple therapeutic potentials, including antioxidative and anti-inflammatory effects in animals. Paraquat (PQ) is the second most widely used herbicide worldwide, but it selectively accumulates in human lungs to cause oxidative injury and fibrosis with high mortality. Here, we analyzed the molecular mechanism of the fibrogenic response to PQ and its inhibition by Res and Nrf2. PQ dose-dependently caused toxicity in normal human bronchial epithelial cells (BEAS-2B), resulting in mitochondrial damage, oxidative stress, and cell death. Res at 10 M markedly inhibited PQ toxicity. PQ at 10 M stimulated production of inflammatory and profibrogenic factors (tumor necrosis factor ␣, interleukin 6, and transforming growth factor ␤1) and induced the transformation of normal human lung fibroblasts (WI38-VA13) to myofibroblasts; both effects were inhibited by Res. Res strongly activated the Nrf2 signaling pathway and induced antioxidant response elementdependent cytoprotective genes. On the other hand, knockout or knockdown of Nrf2 markedly increased PQ-induced cytotoxicity, cytokine production, and myofibroblast transformation and abolished protection by Res. The findings demonstrate that Res attenuates PQ-induced reactive oxygen species production, inflammation, and fibrotic reactions by activating Nrf2 signaling. The study reveals a new pathway for molecular intervention against pulmonary oxidative injury and fibrosis.

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“…These effects can be partially reversed by resveratrol (Ref. 87) or PPARγ-ligands bearing and electrophilic center (Ref. 84).…”

Section: Origin Of Myofibroblastsmentioning

confidence: 99%

Myofibroblast differentiation and survival in fibrotic disease

Kis

Liu

Hagood

2011

Expert Rev. Mol. Med.

188

160

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During wound healing, contractile fibroblasts called myofibroblasts regulate the formation and contraction of granulation tissue; however, pathological and persistent myofibroblast activation, such as occurs in hypertrophic scars or tissue fibrosis, results in loss of function. Many outstanding reviews outline cellular and molecular features of myofibroblasts, and their roles in a variety of diseases. This review will focus on the origins of myofibroblasts and the factors which control their differentiation and prolonged survival in fibrotic tissues. Pulmonary fibrosis is used to illustrate many key points, but examples from other tissues and models are also included. Myofibroblasts emerge mostly from tissue-resident fibroblasts but also from epithelial, endothelial cells or other mesenchymal precursors. Their differentiation is influenced by cytokines, growth factors, extracellular matrix composition and stiffness, and cell surface molecules such as proteoglycans and THY1, among other factors. Many of these effects are modulated by cell contraction. Myofibroblasts resist programmed cell death, promoting their accumulation in fibrotic tissues. The cause of resistance to apoptosis in myofibroblasts is under ongoing investigation, but many of the same stimuli that regulate their differentiation are involved. The contributions of oxidative stress, the WNT - β-catenin pathway and PPARγ to myofibroblast differentiation and survival are increasingly appreciated.

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Resveratrol inhibits transforming growth factor-β–induced proliferation and differentiation of ex vivo human lung fibroblasts into myofibroblasts through ERK/Akt inhibition and PTEN restoration

Cited by 50 publications

References 34 publications

Lipopolysaccharide Induces Lung Fibroblast Proliferation through Toll-Like Receptor 4 Signaling and the Phosphoinositide3-Kinase-Akt Pathway

Lipopolysaccharide Induces Lung Fibroblast Proliferation through Toll-Like Receptor 4 Signaling and the Phosphoinositide3-Kinase-Akt Pathway

Resveratrol Inhibits Paraquat-Induced Oxidative Stress and Fibrogenic Response by Activating the Nuclear Factor Erythroid 2-Related Factor 2 Pathway

Myofibroblast differentiation and survival in fibrotic disease

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