Treatment of Intestinal Fibrosis in Experimental Inflammatory Bowel Disease by the Pleiotropic Actions of a Local Rho Kinase Inhibitor

Holvoet, Tom; Devriese, Sarah; Castermans, Karolien; Boland, Sandro; Leysen, Dirk; Vandewynckel, Yves-Paul; Devisscher, Lindsey; Bossche, Lien Van den; Welden, Sophie Van; Dullaers, Mélissa; Vandenbroucke, Roosmarijn E.; Rycke, Riet De; Geboes, Karel; Bourin, Arnaud; Defert, Olivier; Hindryckx, Pieter; Vos, Martine De; Laukens, Debby

doi:10.1053/j.gastro.2017.06.013

Cited by 105 publications

(89 citation statements)

References 33 publications

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“…Treatment of mice with daily doses of VD preserved the histological architecture of the colon, reduced collagen deposition, and prevented intestinal fibrosis, which reinforces a previous study in a different experimental model [35]. The modulation of the immune response by VD may be involved in its protective effects since intestinal grafts from VD-treated mice showed an altered pattern of macrophage expression characterized by a reduced mRNA expression of the M1 macrophage marker, Cd86, in parallel with a diminished mRNA expression of Il-6, a known pro-fibrotic cytokine [38]. However, the fact that no significant differences in CD86 protein levels were detected among treatments, together with the direct effects of VD on intestinal fibroblasts shown in the present study, strongly suggests a role of VD acting on fibroblasts in its anti-fibrotic effects.…”

Section: Discussionsupporting

confidence: 86%

Diminished Vitamin D Receptor Protein Levels in Crohn’s Disease Fibroblasts: Effects of Vitamin D

et al. 2020

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Vitamin D (VD) deficiency has been associated to Crohn’s disease (CD) pathogenesis, and the exogenous administration of VD improves the course of the disease, but the mechanistic basis of these observations remains unknown. Vitamin D receptor (VDR) mediates most of the biological functions of this hormone, and we aim to analyze here the expression of VDR in intestinal tissue, epithelial cells, and fibroblasts from CD patients. The effects of VD on a fibroblast wound healing assay and murine intestinal fibrosis are also analyzed. Our data show diminished VDR protein levels in surgical resections and epithelial cells from CD patients. In intestinal fibroblasts isolated from damaged tissue of CD patients, we detected enhanced migration and decreased VDR expression compared with both fibroblasts from non-damaged tissue of the same CD patient or control fibroblasts. Treatment with VD increased VDR protein levels, avoided the accelerated migration in CD fibroblasts, and prevented murine intestinal fibrosis induced by the heterotopic transplant model. In conclusion, our study demonstrates diminished VDR protein levels associated with enhanced migration in intestinal fibroblasts from damaged tissue of CD patients. In these cells, VD accumulates VDR and normalizes migration, which supports that CD patients would benefit from the VD anti-fibrotic therapeutic value that we demonstrate in a murine experimental model.

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Section: Discussionsupporting

confidence: 86%

Diminished Vitamin D Receptor Protein Levels in Crohn’s Disease Fibroblasts: Effects of Vitamin D

et al. 2020

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“…Intestinal fibrosis serves as the key pathological determinant in the progression of chronic UC, which referred to overactivation of intestinal stromal cells, persistent depositions of collagen, and thickening of intestinal wall 10,51 . OSM augment resulted in the overexpression of FAP and PDPN in OSMR + stromal cells, which contributed to intestinal fibrosis of IBD patients 15 .…”

Section: Discussionmentioning

confidence: 99%

“…The pathogenesis of UC is multidimensional and linked to the coactions between genetic susceptibility, immune system imbalance, dysfunction of intestinal barrier, and turbulence of microorganisms 6,7 . During the progression and exacerbation of UC, colonic tissue fibrosis, as the fact of Sirius red staining and α-SMA + staining, is considered as the key factor, leading to collagen deposition, destruction of extracellular matrix (ECM), and thickening of the intestinal wall [8][9][10] . The fibrotic development is closely associated with a cascade of processes, including epithelial cells injury and reconstitution, activation of immune cells and mesenchymal cells, as well as angiogenesis and lymphangiogenesis 11 .…”

Section: Introductionmentioning

confidence: 99%

Intervention of oncostatin M-driven mucosal inflammation by berberine exerts therapeutic property in chronic ulcerative colitis

Feng

Chen

et al. 2020

Cell Death Dis

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Ulcerative colitis (UC) is a chronic and etiologically refractory inflammatory gut disorder. Although berberine, an isoquinoline alkaloid, has been revealed to exert protective effects on experimental colitis, the underlying molecular mechanism in chronic intestinal inflammation remains ill-defined. This study was designed to uncover the therapeutic efficacy and immunomodulatory role of berberine in chronic UC. Therapeutic effects of oral administration of berberine were investigated in dextran sodium sulfate (DSS)-induced murine chronic UC and the underlying mechanisms were further identified by si-OSMR transfection in human intestinal stromal cells. Berberine significantly attenuated the experimental symptoms and gut inflammation of chronic UC. Berberine treatment could also maintain the intestinal barrier function and rectify tissue fibrosis. In accordance with infiltrations of antigen-presenting cells (APCs), innate lymphoid cells (ILCs), and activated NK cells in colonic lamina propria, increased expression of OSM and OSMR were observed in the inflamed tissue of chronic UC, which were decreased following berberine treatment. Moreover, berberine inhibited the overactivation of human intestinal stromal cells through OSM-mediated JAK-STAT pathway, which was obviously blocked upon siRNA targeting OSMR. The research provided an infusive mechanism of berberine and illustrated that OSM and OSMR intervention might function as the potential target in chronic UC.

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“…11,79,80 In the T cell transfer model of colitis, anti-TNF monotherapy significantly reduced gut inflammation and the colonic production of pro-inflammatory cytokines but did not significantly reduce collagen deposition or TGF-β1 production. 11 In a previous study of S. typhimurium-infected mice, early levofloxacin eradication after Salmonella infection partially prevented intestinal fibrosis progression. However, delayed eradication failed to prevent intestinal fibrosis progression.…”

Section: Matrix Stiffness Regulating Fibrosis Autopropagationmentioning

confidence: 99%

“…The role of Rho/ROCK/Actin/MRTF/SRF signaling, which is induced by TGF-β1 or matrix stiffness, has been revealed in intestinal fibrosis. 11,51,53,181 ROCK is activated in inflamed and fibrotic tissue in CD. The rectal delivery of a novel small molecule ROCK inhibitor (AMA0825) reversed the established intestinal fibrosis in 2 different murine models of fibrosis by diminishing the TGF-β1-induced MRTF and p38 MAPK activation and increasing autophagy in fibroblasts.…”

Section: Promising Anti-fibrotic Agents For Intestinal Fibrosismentioning

confidence: 99%

Fibrostenotic strictures in Crohn’s disease

2020

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reported in 85%-100% of cases 7,10 and fibrostenotic stricture is the most common indication for surgery in CD. 3,9 Surgical resection is related with major morbidity, higher costs, higher risk of unemployment, and poorer quality of life. 3,11,12 Although the introduction of biologics including anti-TNF, anti-integrin, and anti-interleukin (IL) has modified the disease course of CD in the short term, the long-term outcome of those drugs on the development of fibrostenosis and the need for surgery remains to be elucidated. 5 Fibrostenotic strictures were previously considered an inevitable and irreversible consequence of long-term inflammation in CD patients whose conditions are unresponsive to anti-inflammatory therapies. This paradigm has been changing rapidly due to recent advances in our understanding regarding the process of intestinal fibrosis and the introduction of promising candidates for targeted anti-fibrotic therapy. 1 This review aimed to provide a comprehensive overview of fibrostenotic strictures in CD, including mechanisms and factors that predict its progression, as well as diagnosis and treatment strategies. It also introduces promising anti-fibrotic agents for intestinal fibrosis and discuss the obstacles to be overcome in developing clinically available anti-fibrotic agents for CD stricture.

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Treatment of Intestinal Fibrosis in Experimental Inflammatory Bowel Disease by the Pleiotropic Actions of a Local Rho Kinase Inhibitor

Abstract: Local ROCK inhibition prevents and reverses intestinal fibrosis by diminishing MRTF and p38 MAPK activation and increasing autophagy in fibroblasts. Overall, our results show that local ROCK inhibition is promising for counteracting fibrosis as an add-on therapy for CD.

Cited by 105 publications

References 33 publications

Diminished Vitamin D Receptor Protein Levels in Crohn’s Disease Fibroblasts: Effects of Vitamin D

Diminished Vitamin D Receptor Protein Levels in Crohn’s Disease Fibroblasts: Effects of Vitamin D

Intervention of oncostatin M-driven mucosal inflammation by berberine exerts therapeutic property in chronic ulcerative colitis

Fibrostenotic strictures in Crohn’s disease

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