Cellular and molecular mechanisms of intestinal fibrosis

Speca, Silvia; Giusti, Ilaria; Rieder, Florian; Latella, Giovanni

doi:10.3748/wjg.v18.i28.3635

Cited by 234 publications

(251 citation statements)

References 243 publications

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“…Tissue fibrosis is a progressive, severely debilitating disease characterized by superabundant accumulation of extracellular matrix (ECM) leading to excessive tissue scarring, organ injury, function decline, and even failure (Insel et al, 2012;Speca et al, 2012;Friedman et al, 2013). Recent advances indicate that organ fibroses share core features that include epithelial and endothelial injury and dysfunction; abnormal proliferation of myofibroblasts (MFb), smooth muscle cells and stellate cells, and ECM deposition (Bonner, 2004;Speca et al, 2012;Friedman et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Functions of Galectin-3 and Its Role in Fibrotic Diseases

Gao

2014

J Pharmacol Exp Ther

222

184

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Fibrotic diseases occur in a variety of organs and lead to continuous organ injury, function decline, and even failure. Currently effective treatment options are limited. Galectin-3 (Gal-3) is a pleiotropic lectin that plays an important role in cell proliferation, adhesion, differentiation, angiogenesis, and apoptosis. Accumulating evidence indicates that Gal-3 activates a variety of profibrotic factors, promotes fibroblast proliferation and transformation, and mediates collagen production. Recent studies have defined key roles for Gal-3 in fibrogenesis in diverse organ systems, including liver, kidney, lung, and myocardial. To help set the stage for future research, we review recent advances about the role played by Gal-3 in fibrotic diseases. Herein we discuss the potential profibrotic role of Gal-3, inhibition of which may represent a promising therapeutic strategy against tissue fibrosis.

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Section: Introductionmentioning

confidence: 99%

Functions of Galectin-3 and Its Role in Fibrotic Diseases

Gao

2014

J Pharmacol Exp Ther

222

184

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“…Scleraxis may thus represent a potential target for the development of novel antifibrotic therapies aimed at inhibiting myofibroblast formation. transcription factor; cardiac fibroblast; stretch; migration; proliferation MYOFIBROBLASTS, AS THE ACTIVATED form of fibroblasts, are major mediators of tissue fibrosis in the heart, lungs, dermis, kidneys, and gastrointestinal tract (17,26,29,36,42). Excess deposition of fibrillar collagens in the extracellular matrix (ECM) of these tissues imparts increased stiffness and reduced organ function.…”

mentioning

confidence: 99%

Role of scleraxis in mechanical stretch-mediated regulation of cardiac myofibroblast phenotype

Roché

Nagalingam

Bagchi

et al. 2016

American Journal of Physiology-Cell Physiology

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-The phenotype conversion of fibroblasts to myofibroblasts plays a key role in the pathogenesis of cardiac fibrosis. Numerous triggers of this conversion process have been identified, including plating of cells on solid substrates, cytokines such as transforming growth factor-␤, and mechanical stretch; however, the underlying mechanisms remain incompletely defined. Recent studies from our laboratory revealed that the transcription factor scleraxis is a key regulator of cardiac fibroblast phenotype and extracellular matrix expression. Here we report that mechanical stretch induces type I collagen expression and morphological changes indicative of cardiac myofibroblast conversion, as well as scleraxis expression via activation of the scleraxis promoter. Scleraxis causes phenotypic changes similar to stretch, and the effect of stretch is attenuated in scleraxis null cells. Scleraxis was also sufficient to upregulate expression of vinculin and F-actin, to induce stress fiber and focal adhesion formation, and to attenuate both cell migration and proliferation, further evidence of scleraxis-mediated regulation of fibroblast to myofibroblast conversion. Together, these data confirm that scleraxis is sufficient to promote the myofibroblast phenotype and is a required effector of stretch-mediated conversion. Scleraxis may thus represent a potential target for the development of novel antifibrotic therapies aimed at inhibiting myofibroblast formation. transcription factor; cardiac fibroblast; stretch; migration; proliferation MYOFIBROBLASTS, AS THE ACTIVATED form of fibroblasts, are major mediators of tissue fibrosis in the heart, lungs, dermis, kidneys, and gastrointestinal tract (17,26,29,36,42). Excess deposition of fibrillar collagens in the extracellular matrix (ECM) of these tissues imparts increased stiffness and reduced organ function. Cardiac fibrosis entails a poor prognosis, negatively impacting both systolic and diastolic function and eventually leading to heart failure and death (43). There currently exists no treatment for the arrest or reversal of cardiac fibrosis (38). However, alteration of the myofibroblast phenotype may provide a novel means for the treatment and even reversal of fibrotic lesions in various tissue types (20,21,23,26,34,37,49).In response to myocardial injury, the release of damage factors [such as profibrotic transforming growth factor-␤ (TGF-␤)] and mechanical strain resulting from the loss of ECM integrity induce activation of cardiac fibroblasts and subsequent conversion to the myofibroblast phenotype (11,14,22,25,32). Cardiac myofibroblasts are characterized by hypersynthesis of fibrillar collagens type I and III, increased expression of ␣-smooth muscle actin (␣-SMA), increased adhesions and cell size, reduced proliferation and migration, and the formation of stress fibers (12,18,39,44,46). The morphological and functional changes that cardiac fibroblasts undergo during their conversion to myofibroblasts are critical to the wound healing process following myocardial injury. The loca...

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“…The complexity of all implicated factors is also illustrated by the fact that IFNg was able to induce fibroblast apoptosis together with TNF, in an in vitro model studying fibrosis. 48,49 In contrast, TNF was reported to induce intestinal fibrosis by upregulating collagen accumulation, extending the inflammatory state. 49 …”

Section: Comparison Of Fistula Formation and Intestinal Fibrosismentioning

confidence: 99%

“…48,49 In contrast, TNF was reported to induce intestinal fibrosis by upregulating collagen accumulation, extending the inflammatory state. 49 …”

Section: Comparison Of Fistula Formation and Intestinal Fibrosismentioning

confidence: 99%

The two sides of the coin: Similarities and differences in the pathomechanisms of fistulas and stricture formations in irritable bowel disease

Scharl

Bruckner

Rogler

2016

United European Gastroenterology Journal

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Fistulas and fibrosis or strictures represent frequent complications in irritable bowel disease (IBD) patients. To date, treatment options for fistulas are limited and surgery is often required. Similarly, no preventive treatment for fibrosis and stricture formation has been established. Frequently, stricture formation and fibrosis precede fistula formation, indicating that both processes may be connected or interrelated. Knowledge about the pathology of both processes is limited. A crucial role for the epithelial-to-mesenchymal transition (EMT) in fistula development has been demonstrated. Of note, EMT also plays a major role in the pathogenesis of fibrosis in many organs, and most likely also plays that role in the intestine. In addition, aberrant matrix remodeling, as well as soluble factors such as tumor necrosis factor (TNF), interleukin 13 (IL-13) and tumor growth factor beta (TGFb) were involved, both in the onset of the fistula and fibrosis formation. Both fistulas and fibrosis may occur due to deregulated wound healing mechanisms from chronic and severe intestinal inflammation; however, further research is required to obtain a better understanding of the complex pathophysiology of fistula and intestinal fibrosis formation, to allow the development of new and more effective preventive treatment options for those important disease complications.

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Cellular and molecular mechanisms of intestinal fibrosis

Cited by 234 publications

References 243 publications

Functions of Galectin-3 and Its Role in Fibrotic Diseases

Functions of Galectin-3 and Its Role in Fibrotic Diseases

Role of scleraxis in mechanical stretch-mediated regulation of cardiac myofibroblast phenotype

The two sides of the coin: Similarities and differences in the pathomechanisms of fistulas and stricture formations in irritable bowel disease

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