Thrombin induces epithelial-mesenchymal transition via PAR-1, PKC, and ERK1/2 pathways in A549 cells

Song, Jeong Sup; Kang, Chun; Park, Chan Kwon; Yoon, Hyung Kyu

doi:10.3109/01902148.2013.820809

Cited by 25 publications

(25 citation statements)

References 53 publications

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“…Indeed, after proteolytic removal of the N‐terminal extracellular region, a novel tethered ligand that interacts with the body of the receptor is unmasked. Subsequent transmembrane signalling leads, amongst others, to EMT of alveolar epithelial cells and retinal pigment epithelial cells . Moreover, PAR‐1‐dependent signalling drives fibroblast proliferation and extracellular matrix production in vitro, whereas PAR‐1 deficiency limits liver, lung and skin fibrosis in experimental animal models .…”

Section: Introductionmentioning

confidence: 99%

“…Subsequent transmembrane signalling leads, amongst others, to EMT of alveolar epithelial cells and retinal pigment epithelial cells. [9][10][11] Moreover, PAR-1-dependent signalling drives fibroblast proliferation and extracellular matrix production in vitro, whereas PAR-1 deficiency limits liver, lung and skin fibrosis in experimental animal models. [12][13][14][15] In the kidney, PAR-1 is expressed by endothelial cells, podocytes, mesangial cells, and tubular epithelial cells 16 and we recently showed that PAR-1 potentiates diabetic nephropathy by inducing mesangial cell proliferation and extracellular matrix production.…”

mentioning

confidence: 99%

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Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

Waasdorp

Rooij

Florquin

et al. 2018

J Cellular Molecular Medi

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End‐stage renal disease, the final stage of all chronic kidney disorders, is associated with renal fibrosis and inevitably leads to renal failure and death. Transition of tubular epithelial cells (TECs) into mesenchymal fibroblasts constitutes a proposed mechanism underlying the progression of renal fibrosis and here we assessed whether protease‐activated receptor (PAR)‐1, which recently emerged as an inducer of epithelial‐to‐mesenchymal transition (EMT), aggravates renal fibrosis. We show that PAR‐1 activation on TECs reduces the expression of epithelial markers and simultaneously induces mesenchymal marker expression reminiscent of EMT. We next show that kidney damage was reduced in PAR‐1‐deficient mice during unilateral ureter obstruction (UUO) and that PAR‐1‐deficient mice develop a diminished fibrotic response. Importantly, however, we did hardly observe any signs of mesenchymal transition in both wild‐type and PAR‐1‐deficient mice suggesting that diminished fibrosis in PAR‐1‐deficient mice is not due to reduced EMT. Instead, the accumulation of macrophages and fibroblasts was significantly reduced in PAR‐1‐deficient animals which were accompanied by diminished production of MCP‐1 and TGF‐β. Overall, we thus show that PAR‐1 drives EMT of TECs in vitro and aggravates UUO‐induced renal fibrosis although this is likely due to PAR‐1‐dependent pro‐fibrotic cytokine production rather than EMT.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

Waasdorp

Rooij

Florquin

et al. 2018

J Cellular Molecular Medi

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“…PAR1-mediated activation of PKC and ERK1/2 plays a critical role in thrombin-induced mitogenic, inflammatory, and pro-fibrotic effects 4 23 24 25 . ERK1/2 activation by thrombin follows PKC activation 25 , and in the current experiments, we sought to determine ERK1/2 activity (pERK1/2/tERK1/2) in WT and STC1 Tg lungs 1 week after saline (sham) or bleomycin (BLM) treatment. ERK1/2 activity was significantly increased in the lungs of WT mice after bleomycin treatment.…”

Section: Resultsmentioning

confidence: 99%

Stanniocalcin-1 inhibits thrombin-induced signaling and protects from bleomycin-induced lung injury

Huang

Zhang

et al. 2015

Sci Rep

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Thrombin-induced and proteinase-activated receptor 1 (PAR1)-mediated signaling increases ROS production, activates ERK, and promotes inflammation and fibroblast proliferation in bleomycin-induced lung injury. Stanniocalcin-1 (STC1) activates anti-oxidant pathways, inhibits inflammation and provides cytoprotection; hence, we hypothesized that STC1 will inhibit thrombin/PAR1 signaling and protect from bleomycin-induced pneumonitis. We determined thrombin level and activity, thrombin-induced PAR-1-mediated signaling, superoxide generation and lung pathology after intra-tracheal administration of bleomycin to WT and STC1 Tg mice. Lungs of bleomycin-treated WT mice display: severe pneumonitis; increased generation of superoxide; vascular leak; increased thrombin protein abundance and activity; activation of ERK; greater cytokine/chemokine release and infiltration with T-cells and macrophages. Lungs of STC1 Tg mice displayed none of the above changes. Mechanistic analysis in cultured pulmonary epithelial cells (A549) suggests that STC1 inhibits thrombin-induced and PAR1-mediated ERK activation through suppression of superoxide. In conclusion, STC1 blunts bleomycin-induced rise in thrombin protein and activity, diminishes thrombin-induced signaling through PAR1 to ERK, and inhibits bleomycin-induced pneumonitis. Moreover, our study identifies a new set of cytokines/chemokines, which play a role in the pathogenesis of bleomycin-induced lung injury. These findings broaden the array of potential therapeutic targets for the treatment of lung diseases characterized by thrombin activation, oxidant stress and inflammation.

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“…Strikingly, individual coagulation factors exert profibrotic cellular effects through PARs. Thrombin, as the most studied profibrotic coagulation factor, activates PAR-1, leading to myofibroblast accumulation by activating resident lung fibroblasts, promoting EMT of lung epithelial cells, and/or by inducing differentiation of fibrocytes [36][37][38]. Thrombin is also a potent inducer of several profibrotic cytokines, including TGF-b, connective tissue growth factor, and PDGF [39,40].…”

Section: Coagulation and Pars In The Pathogenesis Of Ipfmentioning

confidence: 99%

Targeting coagulation factor receptors – protease‐activated receptors in idiopathic pulmonary fibrosis

Lin

Borensztajn

Spek

2017

Journal of Thrombosis and Haemostasis

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Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with a 5-year mortality rate of > 50% and unknown etiology. Treatment options remain limited and, currently, only two drugs are available, i.e. nintedanib and pirfenidone. However, both of these antifibrotic agents only slow down the progression of the disease, and do not remarkably prolong the survival of IPF patients. Hence, the discovery of new therapeutic targets for IPF is crucial. Studies exploring the mechanisms that are involved in IPF have identified several possible targets for therapeutic interventions. Among these, blood coagulation factor receptors, i.e. protease-activated receptors (PARs), are key candidates, as these receptors mediate the cellular effects of coagulation factors and play central roles in influencing inflammatory and fibrotic responses. In this review, we will focus on the controversial role of the coagulation cascade in the pathogenesis of IPF. In the light of novel data, we will attempt to reconciliate the apparently conflicting data and discuss the possibility of pharmacologic targeting of PARs for the treatment of fibroproliferative diseases.

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Thrombin induces epithelial-mesenchymal transition via PAR-1, PKC, and ERK1/2 pathways in A549 cells

Cited by 25 publications

References 53 publications

Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

Stanniocalcin-1 inhibits thrombin-induced signaling and protects from bleomycin-induced lung injury

Targeting coagulation factor receptors – protease‐activated receptors in idiopathic pulmonary fibrosis

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