Mechanisms That Mediate the Development of Fibrosis in Patients With Crohnʼs Disease

Li, Chao; Kuemmerle, John F.

doi:10.1097/mib.0000000000000043

Cited by 106 publications

(98 citation statements)

References 83 publications

(116 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Proliferation of myofibroblasts and smooth muscle cells and production of collagen by these cell types are also stimulated by IGF-1 (insulin-like growth factor 1) [69][70][71][72][73][74][75], CTGF (connective tissue growth factor), PDGF (platelet-derived growth factor) and multiple inflammatory cytokines produced in excess in Crohn's disease [27,49,76].…”

Section: Molecular Mediators Of Intestinal Fibrosismentioning

confidence: 99%

Pathogenic aspects and therapeutic avenues of intestinal fibrosis in Crohn's disease

2015

View full text Add to dashboard Cite

In Crohn's disease, one of the two major forms of inflammatory bowel diseases in human beings, persistent and chronic inflammation promotes fibrotic processes thereby facilitating formation of strictures, the most common indication for surgical intervention in this disorder. The pathogenesis of Crohn's disease-associated fibrosis is not fully understood, but variants of genes involved in the recognition of microbial components/products [e.g. CARD15 (caspase-activating recruitment domain 15) and ATG16L1 (autophagy-related 16-like 1)] are associated with this phenotype, and experimental evidence suggests that intestinal fibrosis results from an altered balance between deposition of ECM (extracellular matrix) and degradation of ECM by proteases. Studies have also contributed to identify the main phenotypic and functional alterations of cells involved in the fibrogenic process, as well as molecules that stimulate such cells to produce elevated amounts of collagen and other ECM-related proteins. In the present review, we assess the current knowledge about cellular and molecular mediators of intestinal fibrosis and describe results of recent studies aimed at testing the preventive/therapeutic effect of compounds in experimental models of intestinal fibrosis.

show abstract

Section: Molecular Mediators Of Intestinal Fibrosismentioning

confidence: 99%

Pathogenic aspects and therapeutic avenues of intestinal fibrosis in Crohn's disease

2015

View full text Add to dashboard Cite

show abstract

“…MMPs play a central role in the regulation of multiple cellular functions such as cell proliferation, adhesion, migration, differentiation, angiogenesis, and apoptosis [33] and are capable of digesting extracellular matrix such as collagen and basement membrane components [34] and also acting as cell mediators. Because of its strong destructive ability, the activity of MMPs is strictly regulated by TIMPs [35]. TIMPs are also able to promote the proliferation of a variety of cells including fibroblasts [36].…”

Section: Discussionmentioning

confidence: 99%

Pathological study of chronic pulmonary toxicity induced by intratracheally instilled Asian sand dust (Kosa): possible association of fibrosis with the development of granulomatous lesions

Shimada

Kohara

Naota

et al. 2016

Folia Histochem Cytobiol.

View full text Add to dashboard Cite

Introduction. Exposure to Asian sand dust (ASD) is associated with enhanced pulmonary morbidity and mortality, and the reporting of such cases has rapidly increased in East Asia since 2000. The purpose of the study was to assess chronic lung toxicity induced by ASD. Material and methods. A total of 174 ICR mice were randomly divided into 5 control and 17 exposure groups. Suspensions of low dose (0.2, 0.4 mg) and high dose (3.0 mg) of ASD particles in saline were intratracheally instilled into ICR mice, followed by sacrifice at 24 hours, 1 week, and 1, 2, 3 and 4 months after instillation. Paraffin sections of lung tissues were stained with hematoxylin and eosin and by immunohistochemistry to detect a-smooth muscle actin, collagen III, matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1), CD3, CD20, immunoglobulin G, interleukin-1b and inducible nitric oxide synthase. Results. A lung histological examination revealed similar patterns in the lesions of the groups treated with high (3.0 mg) or low dose (0.4 mg) of ASD. Acute inflammation was observed 24 h after treatment and subsided after 1 week; persistent granulomatous changes were observed at 2 months, focal lymphocytic infiltration at 3 months, and granuloma formation at 4 months. An increase in the size of granulomatous lesions was observed over time and was accompanied by collagen deposition in the lesions. The cytoplasm of macrophages in inflammatory lesions showed positive immunolabeling for MMP-9 at 24 h, 1 and 2 months after instillation of 3.0 mg of ASD. Positive immunolabeling for TIMP-1 was demonstrated in the cytoplasm of macrophages at 2 and 4 months after instillation of 3.0 mg of ASD. These findings suggest association between the expression of MMP-9 and TIMP-1 with the development of lung granulomatous lesions. Conclusions. These findings suggest that collagen deposition resulting from the altered regulation of extracellular matrix is associated with granuloma formation in the lungs of mice treated with ASD.

show abstract

“…Once activated autocrine TGF-β1 production increases and elicits excess extracellular matrix production including collagen I. Activation of intestinal mesenchymal cells also increases their autocrine production of a number cytokines including IL-6, IL-10, IL-12, IL-13, and IL-17a and TNF-α (15). Synthesis of IL-6 increases also in response to IL-1β and TNF-α (16, 17).…”

Section: Introductionmentioning

confidence: 99%

Noncanonical STAT3 Activation Regulates Excess TGF-β1 and Collagen I Expression in Muscle of Stricturing Crohn’s Disease

Iness

Yoon

et al. 2015

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Background & Aims Increased TGF-β1 and TGF-β1-dependent Collagen I production in intestinal mesenchymal muscle cells result in fibrosis in patients with Montreal B2 fibrostenotic Crohn's disease. Numerous cytokines, including IL-6, are produced by activated mesenchymal cells themselves and activate STAT3. The aim of the present study was to determine the mechanisms by which STAT-3-activation might result in intestinal fibrosis. Methods Cytokine levels were measured by ELISA. STAT3 and SOCS3 protein levels were measured by immunoblot, STAT3-TGFB1 DNA-binding activity by ChIP, and TGFB1 transcriptional activity by luciferase reporter assay. TGF-β1, Collagen1α1 and CTGF expression was measured by qRT-PCR. The role of STAT3 activation was determined using STAT3 inhibitor, Stattic, and by transfection of STAT3 mutants. Results Autocrine production of cytokines was increased in muscle cells of B2 phenotype patients from strictures and normal intestine in the same patient and compared to other Crohn's phenotypes, ulcerative colitis and non-Crohn's patients. A unique pattern of STAT3 phosphorylation emerged: high STAT3(S727) and low STAT3(Y705) in strictures and the opposite in unaffected intestine. TGFB1 transcriptional activity was regulated by phospho-STAT3(S727) and was decreased by Stattic or dnSTAT3(S727A). TGF-β1, COL1A1, and CTGF expression was inhibited by Stattic or dnSTAT3(S727A). Treatment of normal muscle cells with IL-6 or expression of constitutively-active STAT3(S727E) phenocopied muscle cells from strictured intestine. Neutralization of autocrine IL-6 reversed STAT3 phosphorylation and TGF-β1 in strictured intestinal muscle. The ability of Stattic to improve development of fibrosis was confirmed in mice with TNBS-induced colitis. Conclusions We observed a unique p-STAT3(S727) response in patients with Montreal B2 Crohn's disease particularly in response to IL-6 leading to increased TGF-β1, collagen and CTGF production in ileal strictures.

show abstract

Mechanisms That Mediate the Development of Fibrosis in Patients With Crohnʼs Disease

Cited by 106 publications

References 83 publications

Pathogenic aspects and therapeutic avenues of intestinal fibrosis in Crohn's disease

Pathogenic aspects and therapeutic avenues of intestinal fibrosis in Crohn's disease

Pathological study of chronic pulmonary toxicity induced by intratracheally instilled Asian sand dust (Kosa): possible association of fibrosis with the development of granulomatous lesions

Noncanonical STAT3 Activation Regulates Excess TGF-β1 and Collagen I Expression in Muscle of Stricturing Crohn’s Disease

Contact Info

Product

Resources

About