T1681 Inflammation-Induced Mucosal Endothelial-to-Mesenchymal Transition (EndoMT): A Novel Mechanism Contributing to the Development of Intestinal Fibrosis

Rieder, Florian; Kessler, Sean P.; Scaldaferri, Franco; Schirbel, Anja; West, Gail; Motte, Carol de la; Fiocchi, Claudio

doi:10.1016/s0016-5085(09)62561-0

Cited by 57 publications

(73 citation statements)

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“…Activation of TGFb, Akt, and/or mTOR pathways has been shown to induce EndMT. [15][16][17]20 As such, it could be an interesting indicator of vascular endothelial cellular activation.…”

Section: Discussionmentioning

confidence: 99%

“…Molecules involved in inflammation, coagulation, cell motility, and endothelial repair are synthesized, with phenotypic changes reminiscent of an endothelial-tomesenchymal transition (EndMT). 3,13,14 Just like its epithelial counterpart, EndMT occurs under different stimuli, [15][16][17] which contribute to fibrogenesis in animal models of renal and cardiac fibrosis. 18,19 The aim of our work was to test the hypothesis that expression of EndMT markers could serve as evidence of current endothelial reaction following DSA binding and/or complement activation and thus help to consolidate the diagnosis of ABMR in renal grafts.…”

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confidence: 99%

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Markers of Endothelial-to-Mesenchymal Transition

Xu‐Dubois

Peltier

Brochériou

et al. 2016

Journal of the American Society of Nephrology

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Antibody-mediated rejection (ABMR) is a leading cause of allograft loss. Treatment efficacy depends on accurate diagnosis at an early stage. However, sensitive and reliable markers of antibody-endothelium interaction during ABMR are not available for routine use. Using immunohistochemistry, we retrospectively studied the diagnostic value of three markers of endothelial-to-mesenchymal transition (EndMT), fascin1, vimentin, and heat shock protein 47, for ABMR in 53 renal transplant biopsy specimens, including 20 ABMR specimens, 24 cell-mediated rejection specimens, and nine normal grafts. We validated our results in an independent set of 74 unselected biopsy specimens. Endothelial cells of the peritubular capillaries in grafts with ABMR expressed fascin1, vimentin, and heat shock protein 47 strongly, whereas those from normal renal grafts did not. The level of EndMT marker expression was significantly associated with current ABMR criteria, including capillaritis, glomerulitis, peritubular capillary C4d deposition, and donor-specific antibodies. These markers allowed us to identify C4d-negative ABMR and to predict late occurrence of disease. EndMT markers were more specific than capillaritis for the diagnosis and prognosis of ABMR and predicted late (up to 4 years after biopsy) renal graft dysfunction and proteinuria. In the independent set of 74 renal graft biopsy specimens, the EndMT markers for the diagnosis of ABMR had a sensitivity of 100% and a specificity of 85%. Fascin1 expression in peritubular capillaries was also induced in a rat model of ABMR. In conclusion, EndMT markers are a sensitive and reliable diagnostic tool for detecting endothelial activation during ABMR and predicting late loss of allograft function.

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“…Activation of TGFb, Akt, and/or mTOR pathways has been shown to induce EndMT. [15][16][17]20 As such, it could be an interesting indicator of vascular endothelial cellular activation.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Markers of Endothelial-to-Mesenchymal Transition

Xu‐Dubois

Peltier

Brochériou

et al. 2016

Journal of the American Society of Nephrology

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“…34,35 In addition, tumor necrosis factor alpha (TNF-a), interleukin-6 (IL-6), and IL-1b also induce the EndMT. 41,56,57 Furthermore, we recently demonstrated that the endotoxin lipopolysaccharide induces the acquisition of fibrotic-like phenotype in ECs. 37 This conversion rises as a potential mechanism that begins endothelial dysfunction during the inflammatory process.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Montorfano

Becerra

Cerro

et al. 2014

Laboratory Investigation

120

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During the pathogenesis of systemic inflammation, reactive oxygen species (ROS) circulate in the bloodstream and interact with endothelial cells (ECs), increasing intracellular oxidative stress. Although endothelial dysfunction is crucial in the pathogenesis of systemic inflammation, little is known about the effects of oxidative stress on endothelial dysfunction. Oxidative stress induces several functions, including cellular transformation. A singular process of cell conversion is tendothelial-to-mesenchymal transition, in which ECs become myofibroblasts, thus losing their endothelial properties and gaining fibrotic behavior. However, the participation of oxidative stress as an inductor of conversion of ECs into myofibroblasts is not known. Thus, we studied the role played by oxidative stress in this conversion and investigated the underlying mechanism. Our results show that oxidative stress induces conversion of ECs into myofibroblasts through decreasing the levels of endothelial markers and increasing those of fibrotic and ECM proteins. The underlying mechanism depends on the ALK5/Smad3/NF-kB pathway. Oxidative stress induces the expression and secretion of TGF-b1 and TGF-b2 and p38 MAPK phosphorylation. Downregulation of TGF-b1 and TGF-b2 by siRNA technology abolished the H 2 O 2 -induced conversion. To our knowledge, this is the first report showing that oxidative stress is able to induce conversion of ECs into myofibroblasts via TGF-b secretion, emerging as a source for oxidative stress-based vascular dysfunction. Thus, oxidative stress emerges as a decisive factor in inducing conversion of ECs into myofibroblasts through a TGF-b-dependent mechanism, changing the ECs protein expression profile, and converting normal ECs into pathological ones. This information will be useful in designing new and improved therapeutic strategies against oxidative stress-mediated systemic inflammatory diseases.

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“…Novel genetic tools in the form of double transgenic mice are available using a genetic marker of cell lineage to irreversibly tag specific cell types expressing both Cre-recombinase under the control of a cell specific promoter and a reporter gene such as LacZ or GFP that can be made functional by exposure to the Cre enzyme (75,123,124). Two recent reports using these constructs lend support to the notion that both epithelial-and endothelial-to-mesenchymal transition occur in animal models of IBD and contribute to intestinal fibrosis (28,115). This approach can be used to tag potential fibroblast precursors and other cell types to determine their possible contribution to the process of intestinal fibrogenesis.…”

Section: New Approaches To the Study Of Experimental Intestinal Fibrosismentioning

confidence: 99%

Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease

Rieder

Kessler

Sans

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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121

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Fibrosis is a serious condition complicating chronic inflammatory processes affecting the intestinal tract. Advances in this field that rely on human studies have been slow and seriously restricted by practical and logistic reasons. As a consequence, well-characterized animal models of intestinal fibrosis have emerged as logical and essential systems to better define and understand the pathophysiology of fibrosis. In point of fact, animal models allow the execution of mechanistic studies as well as the implementation of clinical trials with novel, pathophysiology-based therapeutic approaches. This review provides an overview of the currently available animal models of intestinal fibrosis, taking into consideration the methods of induction, key characteristics of each model, and underlying mechanisms. Currently available models will be classified into seven categories: spontaneous, gene-targeted, chemical-, immune-, bacteria-, and radiation-induced as well as postoperative fibrosis. Each model will be discussed in regard to its potential to create research opportunities to gain insights into the mechanisms of intestinal fibrosis and stricture formation and assist in the development of effective and specific antifibrotic therapies.

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T1681 Inflammation-Induced Mucosal Endothelial-to-Mesenchymal Transition (EndoMT): A Novel Mechanism Contributing to the Development of Intestinal Fibrosis

Cited by 57 publications

References 0 publications

Markers of Endothelial-to-Mesenchymal Transition

Markers of Endothelial-to-Mesenchymal Transition

Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway

Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease

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