scholarly journals The Molecular Mechanism of Transforming Growth Factor-β Signaling for Intestinal Fibrosis: A Mini-Review

2019 ◽  
Vol 10 ◽  
Author(s):  
Sun-Mi Yun ◽  
Seok-Ho Kim ◽  
Eun-Hee Kim
Keyword(s):  
Growth Factor ◽  
Molecular Mechanism ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Intestinal Fibrosis

scholarly journals Murine Precision-cut Intestinal Slices as a Potential Screening Tool for Antifibrotic Drugs

2020 ◽  
Vol 26 (5) ◽  
pp. 678-686 ◽  
Author(s):  
Raditya Iswandana ◽  
Bao Tung Pham ◽  
Su Suriguga ◽  
Theerut Luangmonkong ◽  
Louise A van Wijk ◽  
...  
Keyword(s):  
Growth Factor ◽  
Screening Tool ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Plasminogen Activator Inhibitor 1 ◽  
Intestinal Fibrosis ◽  
Fibrotic Process ◽  
The Impact ◽  
Pai 1 ◽  
Antifibrotic Drugs

Abstract Background Intestinal fibrosis is a hallmark of Crohn’s disease. Here, we investigated the impact of several putative antifibrotic compounds on the expression of fibrosis markers using murine precision-cut intestinal slices. Methods Murine precision-cut intestinal slices were cultured for 48 hours in the presence of profibrotic and/or antifibrotic compounds. The fibrotic process was studied on gene and protein level using procollagen 1a1 (Col1α1), heat shock protein 47 (Hsp47), fibronectin (Fn2), and plasminogen activator inhibitor-1 (Pai-1). The effects of potential antifibrotic drugs mainly inhibiting the transforming growth factor β (TGF-β) pathway (eg, valproic acid, tetrandrine, pirfenidone, SB203580, and LY2109761) and compounds mainly acting on the platelet-derived growth factor (PDGF) pathway (eg, imatinib, sorafenib, and sunitinib) were assessed in the model at nontoxic concentrations. Results Murine precision-cut intestinal slices remained viable for 48 hours, and an increased expression of fibrosis markers was observed during culture, including Hsp47, Fn2, and Pai-1. Furthermore, TGF-β1 stimulated fibrogenesis, whereas PDGF did not have an effect. Regarding the tested antifibrotics, pirfenidone, LY2109761, and sunitinib had the most pronounced impact on the expression of fibrosis markers, both in the absence and presence of profibrotic factors, as illustrated by reduced levels of Col1α1, Hsp47, Fn2, and Pai-1 after treatment. Moreover, sunitinib significantly reduced Hsp47 and Fn2 protein expression and the excretion of procollagen 1. Conclusions Precision-cut intestinal slices can successfully be used as a potential preclinical screening tool for antifibrotic drugs. We demonstrated that sunitinib reduced the expression of several fibrosis markers, warranting further evaluation of this compound for the treatment of intestinal fibrosis.

scholarly journals Interaction between sphingosine kinase/sphingosine 1 phosphate and transforming growth factor-β/Smads pathways in experimental intestinal fibrosis. An in vivo immunohistochemical study

2018 ◽  
Author(s):  
Roberta Sferra ◽  
Simona Pompili ◽  
Luca Ventura ◽  
Caroline Dubuquoy ◽  
Silvia Speca ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Sphingosine Kinase ◽  
Transforming Growth Factor Β ◽  
Chronic Colitis ◽  
Mesenchymal Transition ◽  
Intestinal Fibrosis ◽  
Sphingosine 1 Phosphate

A concomitant action of multiple profibrotic mediators appears crucial in the development and progression of fibrosis. Sphingosine kinase/sphingosine 1 phosphate and transforming growth factor-β/Smads pathways are both involved in pathogenesis of fibrosis in several organs by controlling differentiation of fibroblasts to myofibroblasts and the epithelial to-mesenchymal transition. However, their direct involvement in chronic colitis-associated fibrosis it is not yet known. In this study we evaluated the immunohistochemical expression of some proteins implicated in sphingosine kinase/sphingosine 1 phosphate and transforming growth factor-β/Smads pathways in Dextrane Sodium Sulphate (DSS)-induced colorectal fibrosis in mice. Compared to control mice, DSS-induced chronic colitis mice developed a marked intestinal fibrosis associated with a concomitant overexpression of TGF-β, p-Smad3, α-SMA, collagen I-III, SPHK1, RhoA, PI3K, Akt, p-Akt, p-mTOR. This study highlights the relationship between the two pathways and the possible role of SPHK1 in the intestinal fibrosis.  These results, if confirmed by in vitro studies, may have important clinical implications in the development of new therapeutical approaches in inflammatory bowel disease.

Perianale Fisteln bei CED: vom Mausmodell zur Klinik

2018 ◽  
Vol 75 (5) ◽  
pp. 287-294
Author(s):  
Michael Scharl
Keyword(s):  
Growth Factor ◽  
Morbus Crohn ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 13

Zusammenfassung. Fisteln stellen nach wie vor eine der wichtigsten Komplikationen bei Patienten mit Morbus Crohn dar. Bei mindestens einem Drittel aller Morbus Crohn Patienten treten im Laufe der Erkrankung Fisteln auf. Eine dauerhafte Heilung der Fistel wird jedoch, auch unter Ausschöpfung sämtlicher medikamentöser und chirurgischer Therapieoptionen, nur in rund einem Drittel dieser Patienten erreicht. Der genaue molekulare Mechanismus der Fistelentstehung ist bis heute nicht ganz klar. Aus histopathologischer Sichtweise stellen Fisteln eine röhrenartige Struktur dar, welche von flachen epithelartigen Zellen ausgekleidet ist. Als ursächlicher Entstehungsmechanismus wird dabei die sogenannte epitheliale-zu-mesenchymale Transition (EMT) angesehen und es kann eine starke Expression der Entzündungsmediatoren Tumor Nekrose Faktor, Interleukin-13 und Transforming Growth Factor β in den Fistelarealen nachgewiesen werden. Zusätzlich zu den bereits etablierten, medikamentösen Therapieoptionen, also Antibiotika, Immunmodulatoren und anti-TNF Antikörper, stellt insbesondere der Einsatz der mesenchymalen Stammzelltherapie einen erfolgversprechenden Therapieansatz für die Zukunft dar.

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