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Li Y, Xu F, Fang Y, Cui Y, Zhu Z, Wu Y, Tong Y, Hu J, Zhu L, Shen H. Inflammation-fibrosis interplay in inflammatory bowel disease: mechanisms, progression, and therapeutic strategies. Front Pharmacol 2025; 16:1530797. [PMID: 40093318 PMCID: PMC11906429 DOI: 10.3389/fphar.2025.1530797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 02/05/2025] [Indexed: 03/19/2025] Open
Abstract
Background The incidence of intestinal fibrosis in Inflammatory bowel disease has increased in recent years, and the repair process is complex, leading to substantial economic and social burdens. Therefore, understanding the pathogenesis of intestinal fibrosis and exploring potential therapeutic agents is crucial. Purpose This article reviews the pathogenesis of IBD-related intestinal fibrosis, potential therapeutic targets, and the progress of research on Traditional Chinese Medicine (TCM) in inhibiting intestinal fibrosis. It also provides foundational data for developing innovative drugs to prevent intestinal fibrosis. Methods This article reviews the literature from the past decade on advancements in the cellular and molecular mechanisms underlying intestinal fibrosis. Data for this systematic research were obtained from electronic databases including PubMed, CNKI, SciFinder, and Web of Science. Additionally, a comprehensive analysis was conducted on reports regarding the use of TCM for the treatment of intestinal fibrosis. The study synthesizes and summarizes the research findings, presenting key patterns and trends through relevant charts. Results This study reviewed recent advancements in understanding the cellular and molecular mechanisms of intestinal fibrosis, the active ingredients of TCM that inhibit intestinal fibrosis, the efficacy of TCM formulae in preventing intestinal fibrosis, and dietary modification that may contribute to the inhibition of intestinal fibrosis. Conclusion This article examines the cellular and molecular mechanisms that promote the development of intestinal fibrosis, as well as potential therapeutic targets for its treatment. It also provides a theoretical basis for exploring and utilizing TCM resources in the management of intestinal fibrosis. Through the analysis of various TCM medicines, this article underscores the clinical significance and therapeutic potential of TCM and dietary modifications in treating intestinal fibrosis.
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Affiliation(s)
- Yanan Li
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Feng Xu
- Department of Gastroenterology, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
- Department of Gastroenterology, The Third Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China
| | - Yulai Fang
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuan Cui
- Department of Gastroenterology, Ningxian second People's Hospital, Qing Yang, China
| | - Zhenxing Zhu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuguang Wu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yiheng Tong
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Jingyi Hu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Lei Zhu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Hong Shen
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
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Beck M, Kuwert T, Atzinger A, Gerner M, Hartmann A, Saake M, Uder M, Neurath MF, Atreya R. Discrimination between Inflammatory and Fibrotic Activity in Crohn's Disease-Associated Ileal-Colonic Anastomotic Strictures by Combined Ga-68-FAPI-46 and F-18-FDG-PET/CT Imaging. Visc Med 2025; 41:1-13. [PMID: 39927190 PMCID: PMC11801851 DOI: 10.1159/000542160] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 10/18/2024] [Indexed: 02/11/2025] Open
Abstract
Introduction The development of an intestinal stricture in patients with Crohn's disease represents an important and frequent complication, reflecting the progressive nature of the disease. Depending on the inflammatory and fibrotic composition of the stricture, intensified medical therapy, interventional endoscopy, or surgical intervention is required. However, currently available diagnostic approaches can only assess the level of inflammation, but not the degree of fibrosis, limiting rational therapeutic management of Crohn's disease patients. Recently, prolyl endopeptidase fibroblast activating protein (FAP) has been functionally implicated in fibrotic tissue remodelling, indicating it as a promising target for detection of sites of fibrotic tissue remodelling. Thus, intestinal fibrosis might be visualized using Gallium-68 labelled inhibitors of FAP (FAPI). While F-18-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT is a standard diagnostic tool for visualizing inflammatory processes, we combined Ga-68-FAPI-46-PET/CT and F-18-FDG-PET/CT to differentiate predominantly fibrotic or inflammatory areas in Crohn's disease patients with ileo-colonic strictures. Methods In our study, we analysed three Crohn's disease patients with anastomotic ileo-colonic strictures who underwent both dynamic Ga-68-FAPI-46-PET/CT and static F-18-FDG-PET/CT imaging to assess the level of visualized fibrotic areas within the stricture and differentiate it from inflammatory ones. PET images were analysed both visually and quantitatively. Furthermore, conventional MR enterography and endoscopy were performed in parallel to correlate observed findings. Two of the included patients underwent surgery and the histological specimen were analysed for the level of inflammation and fibrosis, which results were similarly compared to the findings of the PET imaging procedures. Results Different uptake patterns of Ga-68-FAPI-46 could be observed in the anastomotic ileo-colonic strictures of the examined Crohn's disease patients, respectively. Immunohistochemical analyses demonstrated that there was a correlation between the level of Ga-68-FAPI-46 uptake and severity of fibrosis, while FDG uptake correlated with the inflammatory activity in the analysed strictures. Discussion The combination with F-18-FDG-PET/CT represents a promising imaging modality to distinguish inflammation from fibrosis and guide subsequent therapy in stricturing Crohn's disease patients, warranting further studies.
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Affiliation(s)
- Michael Beck
- Department of Nuclear Medicine, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Torsten Kuwert
- Department of Nuclear Medicine, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Armin Atzinger
- Department of Nuclear Medicine, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Maximilian Gerner
- First Department of Medicine, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Arndt Hartmann
- Department of Pathology, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Marc Saake
- Department of Radiology, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Michael Uder
- Department of Radiology, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Markus Friedrich Neurath
- First Department of Medicine, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Raja Atreya
- First Department of Medicine, Erlangen University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
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Li Y, Hu J, Au R, Cheng C, Xu F, Li W, Wu Y, Cui Y, Zhu L, Shen H. Therapeutic Effects of Qingchang Tongluo Decoction on Intestinal Fibrosis in Crohn's Disease: Network Pharmacology, Molecular Docking and Experiment Validation. Drug Des Devel Ther 2024; 18:3269-3293. [PMID: 39081706 PMCID: PMC11287763 DOI: 10.2147/dddt.s458811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 07/01/2024] [Indexed: 08/02/2024] Open
Abstract
Background Qingchang Tongluo Decoction (QTF) is clinically used for the treatment of intestinal fibrosis in Crohn's Disease (CD). However, the role of QTF in CD-associated fibrosis and its potential pharmacological mechanism remains unclear. Purpose The objective of this study was to elucidate the potential mechanism of QTF in treating CD-associated fibrosis, employing a combination of bioinformatics approaches - encompassing network pharmacology and molecular docking - complemented by experimental validation. Methods To investigate the material basis and potential protective mechanism of QTF, a network pharmacology analysis was conducted. The core components and targets of QTF underwent molecular docking analysis to corroborate the findings obtained from network pharmacology. In vitro, a colon fibrotic model was established by stimulating IEC-6 cells with 10 ng/mL of transforming growth factor(TGF-β1). In vivo, an intestinal fibrosis model was induced in BALB/c mice by TNBS. The role of QTF in inhibiting the TGF-β1/Smad signaling pathway was investigated through RT-qPCR, Western blotting, immunohistochemistry staining, and immunofluorescence staining. Results Network pharmacology analysis revealed that QTF could exert its protective effect. Bioinformatics analysis suggested that Flavone and Isoflavone might be the key components of the study. Additionally, AKT1, IL-6, TNF, and VEGFA were identified as potential therapeutic targets. Furthermore, experimental validation and molecular docking were employed to corroborate the results obtained from network pharmacology. RT-qPCR, Immunofluorescence, and Western blotting results demonstrated that QTF significantly improved colon function and inhibited pathological intestinal fibrosis in vivo and in vitro. Conclusion Through the application of network pharmacology, molecular docking, and experimental validation, QTF could be confirmed to inhibit the proliferation of intestinal fibroblasts associated with CD and reduce the expression of Collagen I and VEGFA. This effect is achieved through the attenuation of ECM accumulation, primarily via the inhibition of the TGF-β1/Smad signaling pathway.
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Affiliation(s)
- Yanan Li
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Jingyi Hu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Ryan Au
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
- Academy of Chinese Culture and Health Sciences, Oakland, CA, 94612, USA
| | - Cheng Cheng
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Feng Xu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Weiyang Li
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Yuguang Wu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Yuan Cui
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Lei Zhu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
| | - Hong Shen
- Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, People’s Republic of China
- Jiangsu Provincial Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China
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Rajalingam A, Sekar K, Ganjiwale A. Identification of Potential Genes and Critical Pathways in Postoperative Recurrence of Crohn's Disease by Machine Learning And WGCNA Network Analysis. Curr Genomics 2023; 24:84-99. [PMID: 37994325 PMCID: PMC10662376 DOI: 10.2174/1389202924666230601122334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 04/28/2023] [Accepted: 05/10/2023] [Indexed: 11/24/2023] Open
Abstract
Background Crohn's disease (CD) is a chronic idiopathic inflammatory bowel disease affecting the entire gastrointestinal tract from the mouth to the anus. These patients often experience a period of symptomatic relapse and remission. A 20 - 30% symptomatic recurrence rate is reported in the first year after surgery, with a 10% increase each subsequent year. Thus, surgery is done only to relieve symptoms and not for the complete cure of the disease. The determinants and the genetic factors of this disease recurrence are also not well-defined. Therefore, enhanced diagnostic efficiency and prognostic outcome are critical for confronting CD recurrence. Methods We analysed ileal mucosa samples collected from neo-terminal ileum six months after surgery (M6=121 samples) from Crohn's disease dataset (GSE186582). The primary aim of this study is to identify the potential genes and critical pathways in post-operative recurrence of Crohn's disease. We combined the differential gene expression analysis with Recursive feature elimination (RFE), a machine learning approach to get five critical genes for the postoperative recurrence of Crohn's disease. The features (genes) selected by different methods were validated using five binary classifiers for recurrence and remission samples: Logistic Regression (LR), Decision tree classifier (DT), Support Vector Machine (SVM), Random Forest classifier (RF), and K-nearest neighbor (KNN) with 10-fold cross-validation. We also performed weighted gene co-expression network analysis (WGCNA) to select specific modules and feature genes associated with Crohn's disease postoperative recurrence, smoking, and biological sex. Combined with other biological interpretations, including Gene Ontology (GO) analysis, pathway enrichment, and protein-protein interaction (PPI) network analysis, our current study sheds light on the in-depth research of CD diagnosis and prognosis in postoperative recurrence. Results PLOD2, ZNF165, BOK, CX3CR1, and ARMCX4, are the important genes identified from the machine learning approach. These genes are reported to be involved in the viral protein interaction with cytokine and cytokine receptors, lysine degradation, and apoptosis. They are also linked with various cellular and molecular functions such as Peptidyl-lysine hydroxylation, Central nervous system maturation, G protein-coupled chemoattractant receptor activity, BCL-2 homology (BH) domain binding, Gliogenesis and negative regulation of mitochondrial depolarization. WGCNA identified a gene co-expression module that was primarily involved in mitochondrial translational elongation, mitochondrial translational termination, mitochondrial translation, mitochondrial respiratory chain complex, mRNA splicing via spliceosome pathways, etc.; Both the analysis result emphasizes that the mitochondrial depolarization pathway is linked with CD recurrence leading to oxidative stress in promoting inflammation in CD patients. Conclusion These key genes serve as the novel diagnostic biomarker for the postoperative recurrence of Crohn's disease. Thus, among other treatment options present until now, these biomarkers would provide success in both diagnosis and prognosis, aiming for a long-lasting remission to prevent further complications in CD.
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Affiliation(s)
- Aruna Rajalingam
- Department of Life Sciences, Bangalore University, Bangalore, Karnataka, 560056, India
| | - Kanagaraj Sekar
- Laboratory for Structural Biology and Bio-computing, Computational and Data Sciences, Indian Institute of Science, Bangalore, Karnataka, 560012, India
| | - Anjali Ganjiwale
- Department of Life Sciences, Bangalore University, Bangalore, Karnataka, 560056, India
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Qian W, Xu Y, Wen W, Huang L, Guo Z, Zhu W, Li Y. Exosomal miR-103a-3p from Crohn's Creeping Fat-Derived Adipose-Derived Stem Cells Contributes to Intestinal Fibrosis by Targeting TGFBR3 and Activating Fibroblasts. J Crohns Colitis 2023; 17:1291-1308. [PMID: 36897738 DOI: 10.1093/ecco-jcc/jjad042] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Indexed: 03/11/2023]
Abstract
BACKGROUND AND AIMS Mesenteric adipose tissue hypertrophy is a hallmark of Crohn's disease [CD], and creeping fat [CF] is unique to CD. Adipose-derived stem cells [ASCs] from inflammatory tissue exhibited altered biological functions. The role of ASCs isolated from CF in intestinal fibrosis and the potential mechanism remain unclear. METHODS ASCs were isolated from CF [CF-ASCs] and disease-unaffected mesenteric adipose tissue [Ctrl-ASCs] of patients with CD. A series of in vitro and in vivo experiments were conducted to study the effects of exosomes from CF-ASCs [CF-Exos] on intestinal fibrosis and fibroblast activation. A micro-RNA microarray analysis was performed. Western blot, luciferase assay and immunofluorescence were performed to further detect the underlying mechanisms. RESULTS The results indicated that CF-Exos promoted intestinal fibrosis by activating fibroblasts in a dose-dependent manner. They continuously promoted progression of intestinal fibrosis even after dextran sulphate sodium withdrawal. Further analysis showed that exosomal miR-103a-3p was enriched in CF-Exos and participated in exosome-mediated fibroblast activation. TGFBR3 was identified as a target gene of miR-103a-3p. Mechanistically, CF-ASCs released exosomal miR-103a-3p and promoted fibroblast activation by targeting TGFBR3 and promoting Smad2/3 phosphorylation. We also found that the expression of miR-103a-3p in diseased intestine was positively associated with the degree of CF and fibrosis score. CONCLUSION Our findings show that exosomal miR-103a-3p from CF-ASCs promotes intestinal fibrosis by activating fibroblasts via TGFBR3 targeting, suggesting that CF-ASCs are potential therapeutic targets for intestinal fibrosis in CD.
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Affiliation(s)
- Wenwei Qian
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, No. 305 East Zhongshan Road, Nanjing, PR China
| | - Yihan Xu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, PR China
| | - Weiwei Wen
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, No. 305 East Zhongshan Road, Nanjing, PR China
| | - Liangyu Huang
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China
| | - Zhen Guo
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, PR China
| | - Weiming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, No. 305 East Zhongshan Road, Nanjing, PR China
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, PR China
| | - Yi Li
- Department of General Surgery, Jinling Hospital, Medical School of Southeast University, No. 305 East Zhongshan Road, Nanjing, PR China
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, No. 305 East Zhongshan Road, Nanjing, PR China
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Park SE, Kang S, Paek J, Georgescu A, Chang J, Yi AY, Wilkins BJ, Karakasheva TA, Hamilton KE, Huh DD. Geometric engineering of organoid culture for enhanced organogenesis in a dish. Nat Methods 2022; 19:1449-1460. [PMID: 36280722 PMCID: PMC10027401 DOI: 10.1038/s41592-022-01643-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 09/09/2022] [Indexed: 12/22/2022]
Abstract
Here, we introduce a facile, scalable engineering approach to enable long-term development and maturation of organoids. We have redesigned the configuration of conventional organoid culture to develop a platform that converts single injections of stem cell suspensions to radial arrays of organoids that can be maintained for extended periods without the need for passaging. Using this system, we demonstrate accelerated production of intestinal organoids with significantly enhanced structural and functional maturity, and their continuous development for over 4 weeks. Furthermore, we present a patient-derived organoid model of inflammatory bowel disease (IBD) and its interrogation using single-cell RNA sequencing to demonstrate its ability to reproduce key pathological features of IBD. Finally, we describe the extension of our approach to engineer vascularized, perfusable human enteroids, which can be used to model innate immune responses in IBD. This work provides an immediately deployable platform technology toward engineering more realistic organ-like structures in a dish.
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Affiliation(s)
- Sunghee Estelle Park
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
- NSF Science and Technology Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, USA
| | - Shawn Kang
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Jungwook Paek
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Andrei Georgescu
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
- Vivodyne, Inc., Philadelphia, PA, USA
| | - Jeehan Chang
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
- NSF Science and Technology Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, USA
| | - Alex Yoon Yi
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Benjamin J Wilkins
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Tatiana A Karakasheva
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Kathryn E Hamilton
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Dan Dongeun Huh
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
- NSF Science and Technology Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA, USA.
- Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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Dal Buono A, Faita F, Peyrin-Biroulet L, Danese S, Allocca M. Ultrasound Elastography in Inflammatory Bowel Diseases: A Systematic Review of Accuracy Compared with Histopathological Assessment. J Crohns Colitis 2022; 16:1637-1646. [PMID: 35696668 PMCID: PMC9624288 DOI: 10.1093/ecco-jcc/jjac082] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/09/2022] [Accepted: 06/12/2022] [Indexed: 01/07/2023]
Abstract
BACKGROUND AND AIMS Ultrasound elastography [USE] is an innovative, non-invasive, promptly available, ancillary technique that has been proposed in the evaluation of intestinal fibrosis as a monitorable biomarker, in terms of stiffness. The non-invasive estimate of fibrosis by USE appears appealing for dedicated physicians, in order to optimise the treatments for inflammatory bowel disease [IBD] patients [surgical vs non-surgical]. We aimed to systematically review literature evidence on ultrasound elastography in IBD patients. METHODS For this qualitative systematic review, we searched PubMed, EMBASE, and Scopus to identify all studies, published until October 2021, investigating the application of USE in IBD patients compared with histopathological assessment. RESULTS Overall, 12 papers published between 2011 and 2019 were included. A total of 275 IBD patients were included: 272 Crohn's disease [CD] [98.9%] and three ulcerative colitis [UC] [1.1%]. Seven [58.3%] and four [41.6%] studies investigated strain elastography [SE] and shear wave elastography [SWE], respectively; in one study [0.1%] both techniques were addressed. The histological evaluation was largely conducted on surgical specimens and in two studies endoscopic biopsies were also included. The histological assessment was semi-quantitative in all the included studies, except for two where the fibrosis was evaluated only qualitatively. In 10/12 publications USE could accurately distinguish inflammation from fibrosis in the examined bowel tracts. CONCLUSIONS From the preliminary available data, an overall moderate-to-good accuracy of USE in detecting histological fibrosis [10/12 studies] was found. Point-shear wave elastography has been shown to perform superiorly. Further studies are needed to confirm these evidences.
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Affiliation(s)
- Arianna Dal Buono
- IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy
| | - Francesco Faita
- Italian National Research Council Institute of Clinical Physiology, Pisa, Italy
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, and University Vita-Salute San Raffaele, Milan, Italy
| | - Mariangela Allocca
- Corresponding author: Mariangela Allocca, MD, PhD, IBD Center, Department of Gastroenterology, Ospedale Vita-Salute San Raffaele, IRCCS, Milan, Italy. Tel.: +39026432069; E-mail:
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8
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D'Alessio S, Ungaro F, Noviello D, Lovisa S, Peyrin-Biroulet L, Danese S. Revisiting fibrosis in inflammatory bowel disease: the gut thickens. Nat Rev Gastroenterol Hepatol 2022; 19:169-184. [PMID: 34876680 DOI: 10.1038/s41575-021-00543-0] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/27/2021] [Indexed: 12/11/2022]
Abstract
Intestinal fibrosis, which is usually the consequence of chronic inflammation, is a common complication of inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. In the past few years, substantial advances have been made in the areas of pathogenesis, diagnosis and management of intestinal fibrosis. Of particular interest have been inflammation-independent mechanisms behind the gut fibrotic process, genetic and environmental risk factors (such as the role of the microbiota), and the generation of new in vitro and in vivo systems to study fibrogenesis in the gut. A huge amount of work has also been done in the area of biomarkers to predict or detect intestinal fibrosis, including novel cross-sectional imaging techniques. In parallel, researchers are embarking on developing and validating clinical trial end points and protocols to test novel antifibrotic agents, although no antifibrotic therapies are currently available. This Review presents the state of the art on the most recently identified pathogenic mechanisms of this serious IBD-related complication, focusing on possible targets of antifibrotic therapies, management strategies, and factors that might predict fibrosis progression or response to treatment.
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Affiliation(s)
| | - Federica Ungaro
- Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Daniele Noviello
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Sara Lovisa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.,IBD Centre, Laboratory of Gastrointestinal Immunopathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Laurent Peyrin-Biroulet
- INSERM NGERE, University of Lorraine, Vandoeuvre-les-Nancy, Nancy, France.,Nancy University Hospital, Vandoeuvre-les-Nancy, Nancy, France
| | - Silvio Danese
- Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy. .,University Vita-Salute San Raffaele, Milan, Italy.
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Marafini I, Salvatori S, Troncone E, Scarozza P, Fantini E, Monteleone G. No effect of a liquid diet in the management of patients with stricturing Crohn's disease. Int J Colorectal Dis 2020; 35:1881-1885. [PMID: 32504336 DOI: 10.1007/s00384-020-03650-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/20/2020] [Indexed: 02/04/2023]
Abstract
PURPOSE Patients with stricturing Crohn's disease (CD) may experience episodes of intestinal sub-occlusions, which in many cases lead to surgery. The aim of this study was to examine whether adding a liquid diet to medical therapy could improve the management of patients with stricturing CD. METHODS Medical records of CD outpatients with a small bowel stricture, either receiving (group 1) or not (group 2) a 24-h liquid diet every 10-14 days, were retrospectively analyzed. Number of sub-occlusive episodes, frequency, and timing of intestinal resections for strictures were analyzed. RESULTS During the 12-month follow-up, there was no significant difference in the occurrence of new sub-occlusive episodes between the 2 groups (10/37 patients (27%) in group 1 vs 9/45 patients (20%) in group 2). Similarly, the number of patients undergoing bowel resections for sub-occlusive episodes non-responsive to medical therapy did not statistically differ between the two groups (9 patients (24.3%) in group 1 vs 7 patients (15.5%) in group 2). In group 1, surgeries were equally distributed along the 12-months of follow-up, while 85.7% of patients in group 2 underwent intestinal resection within the first 3 months of follow-up. CONCLUSION Adding a liquid diet to medical therapy does not help management of patients with stricturing CD.
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Affiliation(s)
- Irene Marafini
- Department of Systems Medicine, Gastroenterology Unit, University of Rome "Tor Vergata", Via Montpellier, 1, 00133, Rome, Italy
| | - Silvia Salvatori
- Department of Systems Medicine, Gastroenterology Unit, University of Rome "Tor Vergata", Via Montpellier, 1, 00133, Rome, Italy
| | - Edoardo Troncone
- Department of Systems Medicine, Gastroenterology Unit, University of Rome "Tor Vergata", Via Montpellier, 1, 00133, Rome, Italy
| | - Patrizio Scarozza
- Department of Systems Medicine, Gastroenterology Unit, University of Rome "Tor Vergata", Via Montpellier, 1, 00133, Rome, Italy
| | - Elisa Fantini
- Department of Systems Medicine, Gastroenterology Unit, University of Rome "Tor Vergata", Via Montpellier, 1, 00133, Rome, Italy
| | - Giovanni Monteleone
- Department of Systems Medicine, Gastroenterology Unit, University of Rome "Tor Vergata", Via Montpellier, 1, 00133, Rome, Italy.
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10
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Strictures in Crohn's Disease: From Pathophysiology to Treatment. Dig Dis Sci 2020; 65:1904-1916. [PMID: 32279173 DOI: 10.1007/s10620-020-06227-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 03/19/2020] [Indexed: 12/16/2022]
Abstract
Despite recent advances aimed to treat transmural inflammation in Crohn's disease (CD) patients, the progression to a structuring behavior still represents an issue for clinicians. As inflammation becomes chronic and severe, the attempt to repair damaged tissue can result in an excessive production of extracellular matrix components and deposition of connective tissue, thus favoring the formation of strictures. No specific and accurate clinical predictors or diagnostic tools for intestinal fibrosis exist, and to date, no genetic or serological marker is in routine clinical use. Therefore, intestinal fibrosis is usually diagnosed when it becomes clinically evident and strictures have already occurred. Anti-fibrotic agents such as tranilast, peroxisome proliferator-activated receptor gamma agonists, rho kinase inhibitors, and especially mesenchymal stem cell therapy have provided interesting results, but most of the evidence has been derived from studies performed in vitro. Therefore, current therapy of fibrotic strictures relies mainly on endoscopic and surgical procedures. Although its long-term outcomes may be debated, endoscopic balloon dilation appears to be the safest and most effective approach to treat appropriately selected strictures. The use of endoscopic stricturotomy is currently limited by the expertise needed to perform it and by the few data available in the literature. Some good results have been achieved by the positioning of self-expandable metal stents (SEMS). However, there is no concordance regarding the type of stent to use and for how long it should be left in place. The development of new specific SEMS may lead to better outcomes and to an increased use of this alternative in CD-related strictures.
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11
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Creyns B, Cremer J, De Hertogh G, Boon L, Ferrante M, Vermeire S, Van Assche G, Ceuppens JL, Breynaert C. Fibrogenesis in chronic murine colitis is independent of innate lymphoid cells. IMMUNITY INFLAMMATION AND DISEASE 2020; 8:393-407. [PMID: 32567222 PMCID: PMC7416052 DOI: 10.1002/iid3.321] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/31/2020] [Accepted: 06/03/2020] [Indexed: 12/11/2022]
Abstract
Introduction Insight in the pathogenesis of intestinal fibrosis is an unmet medical need in inflammatory bowel diseases. Studies in murine models and human organ fibrosis point to a potential role of innate lymphoid cells (ILC) in chronic intestinal inflammation and fibrosis. Materials and Methods Dextran sodium sulfate (DSS) in drinking water was used to induce chronic colitis and remodeling in C57Bl/6 wild type (WT), RAG‐deficient, RAG−/− common γ chain deficient and anti‐CD90.2 monoclonal antibody treated RAG−/− mice. Inflammation was scored by macroscopic and histological examination and fibrosis was evaluated by hydroxyproline quantification and histology. Results In RAG−/− mice (which have a normal ILC population but no adaptive immunity), chronic intestinal inflammation and fibrosis developed similarly as in WT mice, with a relative increase in ILC2 during repeated DSS exposure. Chronic colitis could also be induced in the absence of ILC (RAG−/−γc−/− or anti‐CD90.2 treated RAG−/− mice) with no attenuation of fibrosis. Importantly, clinical recovery based on weight gain after stopping DSS exposure was impaired in ILC‐deficient or ILC‐depleted mice. Conclusion These data argue against a profibrotic effect of ILC in chronic colitis, but rather suggest that ILC have a protective and recovery‐enhancing effect after repeated intestinal injury.
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Affiliation(s)
- Brecht Creyns
- Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium.,Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Jonathan Cremer
- Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium.,Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Gert De Hertogh
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium
| | | | - Marc Ferrante
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Gert Van Assche
- Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Jan L Ceuppens
- Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium
| | - Christine Breynaert
- Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium.,Department of General Internal Medicine, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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12
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Iswandana R, Pham BT, Suriguga S, Luangmonkong T, van Wijk LA, Jansen YJM, Oosterhuis D, Mutsaers HAM, Olinga P. Murine Precision-cut Intestinal Slices as a Potential Screening Tool for Antifibrotic Drugs. Inflamm Bowel Dis 2020; 26:678-686. [PMID: 31943022 PMCID: PMC7150673 DOI: 10.1093/ibd/izz329] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Indexed: 12/14/2022]
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.
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Affiliation(s)
- Raditya Iswandana
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands,Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia
| | - Bao Tung Pham
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands,Department of Pharmaceutics, Hanoi University of Pharmacy, Hanoi, Vietnam
| | - Su Suriguga
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Theerut Luangmonkong
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands,Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
| | - Louise A van Wijk
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Yvette J M Jansen
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Dorenda Oosterhuis
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Henricus Antonius Maria Mutsaers
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Peter Olinga
- Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Groningen, the Netherlands,Address correspondence to: Professor Peter Olinga, Division of Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands. E-mail:
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13
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Alaimo A, Rubert J. The Pivotal Role of TRP Channels in Homeostasis and Diseases throughout the Gastrointestinal Tract. Int J Mol Sci 2019; 20:ijms20215277. [PMID: 31652951 PMCID: PMC6862298 DOI: 10.3390/ijms20215277] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/20/2019] [Accepted: 10/22/2019] [Indexed: 12/12/2022] Open
Abstract
The transient receptor potential (TRP) channels superfamily are a large group of proteins that play crucial roles in cellular processes. For example, these cation channels act as sensors in the detection and transduction of stimuli of temperature, small molecules, voltage, pH, and mechanical constrains. Over the past decades, different members of the TRP channels have been identified in the human gastrointestinal (GI) tract playing multiple modulatory roles. Noteworthy, TRPs support critical functions related to the taste perception, mechanosensation, and pain. They also participate in the modulation of motility and secretions of the human gut. Last but not least, altered expression or activity and mutations in the TRP genes are often related to a wide range of disorders of the gut epithelium, including inflammatory bowel disease, fibrosis, visceral hyperalgesia, irritable bowel syndrome, and colorectal cancer. TRP channels could therefore be promising drug targets for the treatment of GI malignancies. This review aims at providing a comprehensive picture of the most recent advances highlighting the expression and function of TRP channels in the GI tract, and secondly, the description of the potential roles of TRPs in relevant disorders is discussed reporting our standpoint on GI tract–TRP channels interactions.
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Affiliation(s)
- Alessandro Alaimo
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Povo (Tn), Italy.
| | - Josep Rubert
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Via Sommarive 9, 38123 Povo (Tn), Italy.
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14
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Ehrhardt K, Steck N, Kappelhoff R, Stein S, Rieder F, Gordon IO, Boyle EC, Braubach P, Overall CM, Finlay BB, Grassl GA. Persistent Salmonella enterica Serovar Typhimurium Infection Induces Protease Expression During Intestinal Fibrosis. Inflamm Bowel Dis 2019; 25:1629-1643. [PMID: 31066456 PMCID: PMC6749888 DOI: 10.1093/ibd/izz070] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Intestinal fibrosis is a common and serious complication of Crohn's disease characterized by the accumulation of fibroblasts, deposition of extracellular matrix, and formation of scar tissue. Although many factors including cytokines and proteases contribute to the development of intestinal fibrosis, the initiating mechanisms and the complex interplay between these factors remain unclear. METHODS Chronic infection of mice with Salmonella enterica serovar Typhimurium was used to induce intestinal fibrosis. A murine protease-specific CLIP-CHIP microarray analysis was employed to assess regulation of proteases and protease inhibitors. To confirm up- or downregulation during fibrosis, we performed quantitative real-time polymerase chain reaction (PCR) and immunohistochemical stainings in mouse tissue and tissue from patients with inflammatory bowel disease. In vitro infections were used to demonstrate a direct effect of bacterial infection in the regulation of proteases. RESULTS Mice develop severe and persistent intestinal fibrosis upon chronic infection with Salmonella enterica serovar Typhimurium, mimicking the pathology of human disease. Microarray analyses revealed 56 up- and 40 downregulated proteases and protease inhibitors in fibrotic cecal tissue. Various matrix metalloproteases, serine proteases, cysteine proteases, and protease inhibitors were regulated in the fibrotic tissue, 22 of which were confirmed by quantitative real-time PCR. Proteases demonstrated site-specific staining patterns in intestinal fibrotic tissue from mice and in tissue from human inflammatory bowel disease patients. Finally, we show in vitro that Salmonella infection directly induces protease expression in macrophages and epithelial cells but not in fibroblasts. CONCLUSIONS In summary, we show that chronic Salmonella infection regulates proteases and protease inhibitors during tissue fibrosis in vivo and in vitro, and therefore this model is well suited to investigating the role of proteases in intestinal fibrosis.
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Affiliation(s)
- Katrin Ehrhardt
- Institute of Medical Microbiology and Hospital Epidemiology and German Center for Infection Research (DZIF), Partner Site Hannover, Hannover Medical School, Hannover, Germany
| | - Natalie Steck
- Institute for Experimental Medicine, Christian-Albrechts University of Kiel, Kiel, Germany, and Research Center Borstel, Borstel, Germany
| | - Reinhild Kappelhoff
- Department of Oral Biological and Medical Sciences, Centre for Blood Research, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada
| | - Stephanie Stein
- Institute for Experimental Medicine, Christian-Albrechts University of Kiel, Kiel, Germany, and Research Center Borstel, Borstel, Germany,Present affiliation: Center for Internal Medicine, I. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Florian Rieder
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute
| | - Ilyssa O Gordon
- Department of Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Erin C Boyle
- Department of Cardiothoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany,Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Peter Braubach
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Christopher M Overall
- Department of Oral Biological and Medical Sciences, Centre for Blood Research, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada
| | - B Brett Finlay
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada
| | - Guntram A Grassl
- Institute of Medical Microbiology and Hospital Epidemiology and German Center for Infection Research (DZIF), Partner Site Hannover, Hannover Medical School, Hannover, Germany,Address correspondence to: Guntram A. Grassl, PhD, Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany ()
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15
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Yun SM, Kim SH, Kim EH. The Molecular Mechanism of Transforming Growth Factor-β Signaling for Intestinal Fibrosis: A Mini-Review. Front Pharmacol 2019; 10:162. [PMID: 30873033 PMCID: PMC6400889 DOI: 10.3389/fphar.2019.00162] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 02/11/2019] [Indexed: 01/01/2023] Open
Abstract
Inflammatory bowel disease is known as the most chronic inflammatory disorder in colon, which subsequently progresses to intestinal obstruction and fistula formation. Many studies to date for the treatment of IBD have been focused on inflammation. However, most of the anti-inflammatory agents do not have anti-fibrotic effects and could not relieve intestinal stricture in IBD patients. Because preventing or reversing intestinal fibrosis in IBD is a major therapeutic target, we analyzed the papers focusing on TGF-β signaling in intestinal fibrosis. TGF-β is a good candidate to treat the intestinal fibrosis in IBD which involves TGF-β signaling pathway, EMT, EndMT, ECM, and other regulators. Understanding the mechanism involved in TGF-β signaling will contribute to the treatment and diagnosis of intestinal fibrosis occurring in IBD as well as the understanding of the molecular mechanisms underlying the pathogenesis.
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Affiliation(s)
- Sun-Mi Yun
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, South Korea
| | - Seok-Ho Kim
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, South Korea
| | - Eun-Hee Kim
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, South Korea
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16
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Wilkens R, Hagemann-Madsen RH, Peters DA, Nielsen AH, Nørager CB, Glerup H, Krogh K. Validity of Contrast-enhanced Ultrasonography and Dynamic Contrast-enhanced MR Enterography in the Assessment of Transmural Activity and Fibrosis in Crohn's Disease. J Crohns Colitis 2018; 12:48-56. [PMID: 28981627 DOI: 10.1093/ecco-jcc/jjx111] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 08/01/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS Increased small intestinal wall thickness correlates with both inflammatory activity and fibrosis in Crohn's disease [CD]. Assessment of perfusion holds promise as an objective marker distinguishing between the two conditions. Our primary aim was to determine if relative bowel wall perfusion measurements correlate with histopathological scores for inflammation or fibrosis in CD. METHODS A total of 25 patients were investigated before elective surgery for small intestinal CD. Unenhanced ultrasonography [US] and magnetic resonance enterography [MRE] were applied to describe bowel wall thickness. Perfusion was assessed with contrast-enhanced US [CEUS] and dynamic contrast-enhanced MRE [DCE-MRE]. Histopathology was used as gold standard. RESULTS Compared with histopathology, the mean wall thickness was 0.4 mm greater on US [range -0.3 to 1.0, p = 0.24] and 1.4 mm greater on MR [0.4 to 2.3, p = 0.006]. No correlation was found between the severity of inflammation or fibrosis on histopathology, and either DCE-MRE [r = -0.13, p = 0.54 for inflammation and r = 0.41, p = 0.05 for fibrosis] or CEUS [r = 0.16, p = 0.45 for inflammation and r = -0.28, p = 0.19 for fibrosis]. Wall thickness assessed with US was correlated with both histological inflammation [r = 0.611, p = 0.0012] and fibrosis [r = 0.399, p = 0.048]. The same was not true for MR [r = 0.41, p = 0.047 for inflammation and r = 0.29, p = 0.16 for fibrosis]. CONCLUSIONS Bowel wall thickness assessed with US is a valid marker of inflammation in small intestinal CD. However, relative contrast enhancement of US or of MRE cannot distinguish between inflammatory activity and fibrosis.
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Affiliation(s)
- Rune Wilkens
- University Research Clinic for Innovative Patient Pathways, Silkeborg Regional Hospital, Silkeborg, Denmark.,Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Rikke H Hagemann-Madsen
- Department of Clinical Pathology, Lillebaelt Hospital, Vejle, Denmark.,Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | - David A Peters
- Department of Clinical Engineering, Aarhus University Hospital, Aarhus, Denmark
| | - Agnete H Nielsen
- University Research Clinic for Innovative Patient Pathways, Silkeborg Regional Hospital, Silkeborg, Denmark
| | - Charlotte B Nørager
- Department of Colorectal Surgery P, Aarhus University Hospital, Aarhus, Denmark
| | - Henning Glerup
- University Research Clinic for Innovative Patient Pathways, Silkeborg Regional Hospital, Silkeborg, Denmark
| | - Klaus Krogh
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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17
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Comparison of CT enterography and MR enterography imaging features of active Crohn disease in children and adolescents. Pediatr Radiol 2017; 47:1321-1328. [PMID: 28470387 DOI: 10.1007/s00247-017-3876-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Revised: 02/20/2017] [Accepted: 04/20/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Assessment for active Crohn disease by CT enterography and MR enterography relies on identifying mural and perienteric imaging features. OBJECTIVE To evaluate the performance of established imaging features of active Crohn disease in children and adolescents on CT and MR enterography compared with histological reference. MATERIALS AND METHODS We included patients ages 18 years and younger who underwent either CT or MR enterography from 2007 to 2014 and had endoscopic biopsy within 28 days of imaging. Two pediatric radiologists blinded to the histological results reviewed imaging studies and scored the bowel for the presence or absence of mural features (wall thickening >3 mm, mural hyperenhancement) and perienteric features (mesenteric hypervascularity, edema, fibrofatty proliferation and lymphadenopathy) of active disease. We performed univariate analysis and multivariate logistic regression to compare imaging features with histological reference. RESULTS We evaluated 452 bowel segments (135 from CT enterography, 317 from MR enterography) from 84 patients. Mural imaging features had the highest association with active inflammation both for MR enterography (wall thickening had 80% accuracy, 69% sensitivity and 91% specificity; mural hyperenhancement had 78%, 53% and 96%, respectively) and CT enterography (wall thickening had 84% accuracy, 72% sensitivity and 91% specificity; mural hyperenhancement had 76%, 51% and 91%, respectively), with perienteric imaging features performing significantly worse on MR enterography relative to CT enterography (P < 0.001). CONCLUSION Mural features are predictors of active inflammation for both CT and MR enterography, while perienteric features can be distinguished better on CT enterography compared with MR enterography. This likely reflects the increased conspicuity of the mesentery on CT enterography and suggests that mural features are the most reliable imaging features of active Crohn disease in children and adolescents.
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18
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Kurahara LH, Hiraishi K, Sumiyoshi M, Doi M, Hu Y, Aoyagi K, Jian Y, Inoue R. Significant contribution of TRPC6 channel-mediated Ca 2+ influx to the pathogenesis of Crohn's disease fibrotic stenosis. J Smooth Muscle Res 2017; 52:78-92. [PMID: 27818466 PMCID: PMC5321852 DOI: 10.1540/jsmr.52.78] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Intestinal fibrosis is an intractable complication of Crohn's disease (CD), and, when occurring excessively, causes severe intestinal obstruction that often necessitates surgical resection. The fibrosis is characterized by an imbalance in the turnover of extracellular matrix (ECM) components, where intestinal fibroblasts/myofibroblasts play active roles in ECM production, fibrogenesis and tissue remodeling, which eventually leads to the formation of stenotic lesions. There is however a great paucity of knowledge about how intestinal fibrosis initiates and progresses, which hampers the development of effective pharmacotherapies against CD. Recently, we explored the potential implications of transient receptor potential (TRP) channels in the pathogenesis of intestinal fibrosis, since they are known to act as cellular stress sensors/transducers affecting intracellular Ca2+ homeostasis/dynamics, and are involved in a broad spectrum of cell pathophysiology including inflammation and tissue remodeling. In this review, we will place a particular emphasis on the intestinal fibroblast/myofibroblast TRPC6 channel to discuss its modulatory effects on fibrotic responses and therapeutic potential for anti-fibrotic treatment against CD-related stenosis.
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Affiliation(s)
- Lin Hai Kurahara
- Department of Physiology, Fukuoka University School of Medicine, Fukuoka 814-0180, Japan
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19
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Wei SC, Chang TA, Chao TH, Chen JS, Chou JW, Chou YH, Chuang CH, Hsu WH, Huang TY, Hsu TC, Lin CC, Lin HH, Lin JK, Lin WC, Ni YH, Shieh MJ, Shih IL, Shun CT, Tsang YM, Wang CY, Wang HY, Weng MT, Wu DC, Wu WC, Yen HH, Wong JM. Management of Crohn's disease in Taiwan: consensus guideline of the Taiwan Society of Inflammatory Bowel Disease. Intest Res 2017; 15:285-310. [PMID: 28670226 PMCID: PMC5478754 DOI: 10.5217/ir.2017.15.3.285] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 05/02/2017] [Accepted: 05/02/2017] [Indexed: 12/12/2022] Open
Abstract
Crohn's disease (CD) is a chronic relapsing and remitting inflammatory disease of the gastrointestinal tract. CD is rare in Taiwan and other Asian countries, but its prevalence and incidence have been steadily increasing. A steering committee was established by the Taiwan Society of Inflammatory Bowel Disease to formulate statements on the diagnosis and management of CD taking into account currently available evidence and the expert opinion of the committee. Thorough clinical, endoscopic, and histological assessments are required for accurate diagnosis of CD. Computed tomography and magnetic resonance imaging are complementary to endoscopic evaluation for disease staging and detecting complications. The goals of CD management are to induce and maintain remission, reduce the risk of complications, and improve quality of life. Corticosteroids are the mainstay for inducing re-mission. Immunomodulating and biologic therapies should be used to maintain remission. Patients should be evaluated for hepatitis B virus and tuberculosis infection prior to treatment and receive regular surveillance for cancer. These consensus statements are based on current local evidence with consideration of factors, and could be serve as concise and practical guidelines for supporting clinicians in the management of patients with CD in Taiwan.
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Affiliation(s)
- Shu-Chen Wei
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ting-An Chang
- Department of Pathology, Taipei City Hospital Renai Branch, Taipei, Taiwan
| | - Te-Hsin Chao
- Division of Colorectal Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Jinn-Shiun Chen
- Division of Colorectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Jen-Wei Chou
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Yenn-Hwei Chou
- Division of General Surgery, Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Chiao-Hsiung Chuang
- Department of Internal Medicine, National Cheng Kung University Hospital, National Cheng Kung University College of Medicine, Tainan, Taiwan
| | - Wen-Hung Hsu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Municipal Hsiaokang Hospital, Kaohsiung, Taiwan
| | - Tien-Yu Huang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Tzu-Chi Hsu
- Division of Colon and Rectal Surgery, Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan
| | - Chun-Chi Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hung-Hsin Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, National Yang-Ming University, Taipei, Taiwan
| | - Jen-Kou Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Wei-Chen Lin
- Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Ming-Jium Shieh
- Department of Oncology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - I-Lun Shih
- Department of Medical Imaging, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chia-Tung Shun
- Department of Pathology and Forensic Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yuk-Ming Tsang
- Division of Medical Imaging, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Cheng-Yi Wang
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Horng-Yuan Wang
- Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan.,MacKay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan.,MacKay Medical College, New Taipei City, Taiwan
| | - Meng-Tzu Weng
- Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Deng-Chyang Wu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Wen-Chieh Wu
- Division of Gastroenterology, Department of Medicine, Taipei City Hospital Renai Branch, Taipei, Taiwan
| | - Hsu-Heng Yen
- Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Jau-Min Wong
- Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
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20
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Koo JB, Nam MO, Jung Y, Yoo J, Kim DH, Kim G, Shin SJ, Lee KM, Hahm KB, Kim JW, Hong SP, Lee KJ, Yoo JH. Anti-fibrogenic effect of PPAR-γ agonists in human intestinal myofibroblasts. BMC Gastroenterol 2017; 17:73. [PMID: 28592228 PMCID: PMC5463383 DOI: 10.1186/s12876-017-0627-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 05/19/2017] [Indexed: 12/30/2022] Open
Abstract
Background Intestinal fibrosis is a serious complication of inflammatory bowel disease, including Crohn’s disease and ulcerative colitis. There is no specific treatment for intestinal fibrosis. Studies have indicated that peroxisome proliferator-activated receptor- γ (PPAR-γ) agonists have anti-fibrogenic properties in organs besides the gut; however, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of PPAR-γ agonists on human primary intestinal myofibroblasts (HIFs). Methods HIFs were isolated from normal colonic tissue of patients undergoing resection due to colorectal cancer. HIFs were treated with TGF-β1 and co-incubated with or without one of two synthetic PPAR-γ agonists, troglitazone or rosiglitazone. mRNA and protein expression of procollagen1A1, fibronectin, and α-smooth muscle actin were determined by semiquantitative reverse transcription-polymerase chain reaction and Western blot. LY294002 (Akt inhibitor) was used to examine whether Akt phosphorylation was a downstream mechanism of TGF-β1 induced expression of procollagen1A1, fibronectin, and α-smooth muscle actin in HIFs. The irreversible PPAR-γ antagonist GW9662 was used to investigate whether the effect of PPAR-γ agonists was PPAR-γ dependent. Results Both PPAR-γ agonists reduced the TGF-β1-induced expression of α-smooth muscle actin which was integrated into stress fibers in HIFs, as determined by actin microfilaments fluorescent staining and α-smooth muscle actin-specific immunocytochemistry. PPAR-γ agonists also inhibited TGF-β1-induced mRNA and protein expressions of procollagen1A1, fibronectin, and α-smooth muscle actin. TGF-β1 stimulation increased phosphorylation of downstream signaling molecules Smad2, Akt, and ERK. TGF-β1 induced synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin through a phosphatidylinositol 3-kinase/Akt-dependent mechanism. PPAR-γ agonists down regulated fibrogenesis, as shown by inhibition of Akt and Smad2 phosphorylation. This anti-fibrogenic effect was PPAR-γ independent. Conclusions Troglitazone and rosiglitazone suppress TGF-β1-induced synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin in HIFs and may be useful in treating intestinal fibrosis. Electronic supplementary material The online version of this article (doi:10.1186/s12876-017-0627-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jun Bon Koo
- Clinical Research Center, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | - Myeong-Ok Nam
- Department of Microbiology, Institute of Basic Medical Sciences, School of Medicine, CHA University, Seongnam, South Korea
| | - Younshin Jung
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea
| | - Jongman Yoo
- Department of Microbiology, Institute of Basic Medical Sciences, School of Medicine, CHA University, Seongnam, South Korea
| | - Duk Hwan Kim
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea
| | - Gwangil Kim
- Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | - Sung Jae Shin
- Department of Gastroenterology, Ajou University School of Medicine, 164, World Cup-ro, Yeongtong-gu, Suwon, 443-380, South Korea
| | - Kee Myung Lee
- Department of Gastroenterology, Ajou University School of Medicine, 164, World Cup-ro, Yeongtong-gu, Suwon, 443-380, South Korea
| | - Ki Baik Hahm
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea
| | - Jong Woo Kim
- Department of Surgery, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | - Sung Pyo Hong
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea
| | - Kwang Jae Lee
- Department of Gastroenterology, Ajou University School of Medicine, 164, World Cup-ro, Yeongtong-gu, Suwon, 443-380, South Korea.
| | - Jun Hwan Yoo
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea.
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21
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Organoid-based epithelial to mesenchymal transition (OEMT) model: from an intestinal fibrosis perspective. Sci Rep 2017; 7:2435. [PMID: 28550311 PMCID: PMC5446415 DOI: 10.1038/s41598-017-02190-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 04/13/2017] [Indexed: 12/13/2022] Open
Abstract
The current in vitro or in vivo intestinal fibrosis models have many limitations. Recent advancements in the isolation and culturing of organoids has led to development of various three-dimensional (3D) intestinal disease models with in vivo physiology. In this study, we generated an organoid-based epithelial to mesenchymal transition (OEMT) model, which could be used as a novel intestinal fibrosis model. Intestinal epithelial organoids (IEOs) were isolated and cultured from the small intestines of normal mice. IEOs were treated with transforming growth factor- β1 (TGF-β1) or Tumor necrosis factor-α (TNF-α) to evaluate their phenotypic change. Raw 264.7 cells (macrophage) stimulated with lipopolysaccharide were co-cultured with IEOs in growth media with or without TGF-β1. TGF-β1 alone slightly induced epithelial to mesenchymal transition (EMT) in the IEOs but mainly disrupted them. Macrophage released cytokines synergistically induced mesenchymal phenotypic changes in TGF-β1 stimulated intestinal organoids. TNF-α and TGF-β1 synergistically induced proliferation of mesenchymal cells as well as EMT in the IEOs. We generated a novel OEMT model based on our finding that TNF-α and TGF-β synergistically induce type 2 EMT in IEOs. This 3D EMT model with in vivo physiology could be used to study EMT associated intestinal fibrosis.
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22
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Ultrasound Shear Wave Elastography and Contrast Enhancement: Effective Biomarkers in Crohn's Disease Strictures. Inflamm Bowel Dis 2017; 23:421-430. [PMID: 28129289 DOI: 10.1097/mib.0000000000001020] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Inflammation, fibrosis, and muscular hypertrophy lead to thickened bowel in Crohn's disease forming strictures. Ultrasound shear wave elastography (SWE) measures bowel wall stiffness. Contrast-enhanced ultrasound (CEUS) uniquely detects bowel wall inflammation. We aim to correlate SWE of ileal Crohn's disease in vivo to CEUS peak enhancement and pathology grades of inflammation, fibrosis, and muscular hypertrophy. METHODS In a prospective institutional review board-approved study, 105 consecutive ileal patients with Crohn's disease received ultrasound. At maximal bowel wall thickness (>4 mm), SWE and CEUS were performed. Fifteen patients had ileal resection within a mean time interval of 71.0 ± 66.9 days. Pathology scores for inflammation, fibrosis, and muscular hypertrophy were compared with SWE and CEUS measurements. RESULTS Mean in vivo SWE velocity for patients with and without surgery was 2.8 ± 0.7 and 2.2 ± 0.8 m/s (P < 0.01), respectively. In all ileal specimens, chronic exceeded active inflammatory change (P < 0.001). There was an inverse relationship between CEUS peak enhancement and both fibrosis, r = -0.59, P = 0.02, and SWE velocity measurements, r = -0.61, P = 0.03. Strictured bowel specimens had more smooth muscle hypertrophy than fibrosis, P < 0.001. There was moderate correlation between SWE and muscular hypertrophy, r = 0.59, P = 0.02 and no significant relationship between SWE and fibrosis scores (P > 0.05). CONCLUSIONS Stiffer bowel from smooth muscle hypertrophy increases SWE measurements. We report a novel relation of high SWE with muscle hypertrophy, and inverse relationship with CEUS peak enhancement; providing differentiation between active and chronic bowel wall inflammation to improve selection between medical therapy and surgery.
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Wilkens R, Peters DA, Nielsen AH, Hovgaard VP, Glerup H, Krogh K. Dynamic Contrast-Enhanced Magnetic Resonance Enterography and Dynamic Contrast-Enhanced Ultrasonography in Crohn's Disease: An Observational Comparison Study. Ultrasound Int Open 2017; 3:E13-E24. [PMID: 28286879 PMCID: PMC5340279 DOI: 10.1055/s-0042-123841] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 09/19/2016] [Accepted: 12/04/2016] [Indexed: 12/12/2022] Open
Abstract
Purpose e Cross-sectional imaging methods are important for objective evaluationof small intestinal inflammationinCrohn'sdisease(CD).The primary aim was to compare relative parameters of intestinal perfusion between contrast-enhanced ultrasonography (CEUS) and dynamic contrast-enhanced magnetic resonance enterography (DCE-MRE) in CD. Furthermore, we aimed at testing the repeatability of regions of interest (ROIs) for CEUS. Methods This prospective study included 25 patients: 12 females (age: 37, range: 19-66) with moderate to severe CD and a bowel wall thickness>3mm evaluated with DCE-MRE and CEUS. CEUS bolus injection was performed twice for repeatability and analyzed in VueBox®. Correlations between modalities were described with Spearman's rho, limits of agreement(LoA) and intraclass correlation coefficient(ICC). ROIrepeatability for CEUS was assessed. Results s The correlation between modalities was good and very good for bowel wall thickness (ICC=0.71, P<0.001) and length of the inflamed segment (ICC=0.89, P<0.001). Moderate-weak correlations were found for the time-intensity curve parameters: peak intensity (r=0.59, P=0.006), maximum wash-in-rate (r=0.62, P=0.004), and wash-in perfusion index (r=0.47, P=0.036). Best CEUS repeatability for peak enhancement was a mean difference of 0.73 dB (95% CI: 0.17 to 1.28, P=0.01) and 95% LoA from -3.8 to 5.3 dB. Good quality of curve fit improved LoA to -2.3 to 2.8 dB. Conclusion The relative perfusion of small intestinal CD assessed with DCE-MRE and CEUS shows only a moderate correlation. Applying strict criteria for ROIs is important and allows for good CEUS repeatability.
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Affiliation(s)
- Rune Wilkens
- Divisions of Medicine and Radiology, Diagnostic Centre, Silkeborg Regional
Hospital, University Research Clinic for Innovative Diagnostic Pathways, Silkeborg,
Denmark
- Department of Hepatology and Gastroenterology, Aarhus University Hospital,
Aarhus C, Denmark
| | - David A. Peters
- Department of Clinical Engineering, Aarhus University Hospital, Aarhus N,
Denmark
| | - Agnete H. Nielsen
- Divisions of Medicine and Radiology, Diagnostic Centre, Silkeborg Regional
Hospital, University Research Clinic for Innovative Diagnostic Pathways, Silkeborg,
Denmark
| | - Valeriya P. Hovgaard
- Divisions of Medicine and Radiology, Diagnostic Centre, Silkeborg Regional
Hospital, University Research Clinic for Innovative Diagnostic Pathways, Silkeborg,
Denmark
| | - Henning Glerup
- Divisions of Medicine and Radiology, Diagnostic Centre, Silkeborg Regional
Hospital, University Research Clinic for Innovative Diagnostic Pathways, Silkeborg,
Denmark
| | - Klaus Krogh
- Department of Hepatology and Gastroenterology, Aarhus University Hospital,
Aarhus C, Denmark
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Li G, Ren J, Hu Q, Deng Y, Chen G, Guo K, Li R, Li Y, Wu L, Wang G, Gu G, Li J. Oral pirfenidone protects against fibrosis by inhibiting fibroblast proliferation and TGF-β signaling in a murine colitis model. Biochem Pharmacol 2016; 117:57-67. [DOI: 10.1016/j.bcp.2016.08.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 08/02/2016] [Indexed: 12/16/2022]
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25
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Rieder F, Latella G, Magro F, Yuksel ES, Higgins PDR, Di Sabatino A, de Bruyn JR, Rimola J, Brito J, Bettenworth D, van Assche G, Bemelman W, d'Hoore A, Pellino G, Dignass AU. European Crohn's and Colitis Organisation Topical Review on Prediction, Diagnosis and Management of Fibrostenosing Crohn's Disease. J Crohns Colitis 2016; 10:873-885. [PMID: 26928961 DOI: 10.1093/ecco-jcc/jjw055] [Citation(s) in RCA: 188] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 02/16/2016] [Indexed: 01/24/2023]
Abstract
This ECCO topical review of the European Crohn's and Colitis Organisation [ECCO] focused on prediction, diagnosis, and management of fibrostenosing Crohn's disease [CD]. The objective was to achieve evidence-supported, expert consensus that provides guidance for clinical practice.
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Affiliation(s)
- Florian Rieder
- Department of Pathobiology, Lerner Research Institute, Cleveland, OH, USA Department of Gastroenterology, Hepatology & Nutrition, Lerner Research Institute, Cleveland, OH, USA
| | - Giovanni Latella
- Department of Life, Health and Environmental Sciences, Gastroenterology Unit, University of L'Aquila, L'Aquila, Italy
| | - Fernando Magro
- Department of Pharmacology & Therapeutics, Department of Gastroenterology, Faculty of Medicine University of Porto, Porto, Portugal
| | - Elif S Yuksel
- Department of Gastroenterology, Izmir Ataturk Teaching and Research Hospital-Katip Celebi University, Izmir, Turkey
| | - Peter D R Higgins
- Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA
| | - Antonio Di Sabatino
- First Department of Internal Medicine, St Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Jessica R de Bruyn
- Academic Medical Center Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
| | - Jordi Rimola
- Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Jorge Brito
- Department of Radiology, Centro Hospitalar do Algarve, Lagos, Portugal
| | | | - Gert van Assche
- Division of Gastroenterology, University of Leuven, Leuven, Belgium
| | - Willem Bemelman
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - Andre d'Hoore
- Department of Abdominal Surgery, University Hospital Gasthuisberg, Leuven, Belgium
| | - Gianluca Pellino
- Department of Medicine 1, Agaplesion Markus Hospital, Frankfurt, Germany
| | - Axel U Dignass
- Department of Pathobiology, Lerner Research Institute, Cleveland, OH, USA
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Jacob N, Targan SR, Shih DQ. Cytokine and anti-cytokine therapies in prevention or treatment of fibrosis in IBD. United European Gastroenterol J 2016; 4:531-40. [PMID: 27536363 DOI: 10.1177/2050640616649356] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 04/19/2016] [Indexed: 12/18/2022] Open
Abstract
The frequency of fibrosing Crohn's disease (CD) is significant, with approximately 40% of CD patients with ileal disease developing clinically apparent strictures throughout their lifetime. Although strictures may be subdivided into fibrotic, inflammatory, or mixed forms, despite immunosuppressive therapy in CD patients in the form of steroids or immunomodulators, the frequency of fibrostenosing complications has still remained significant. A vast number of genetic and epigenetic variables are thought to contribute to fibrostenosing disease, including those that affect cytokine biology, and therefore highlight the complexity of disease, but also shed light on targetable pathways. Exclusively targeting fibrosis may be difficult, however, because of the relatively slow evolution of fibrosis in CD, and the potential adverse effects of inhibiting pathways involved in tissue repair and mucosal healing. Acknowledging these caveats, cytokine-targeted therapy has become the mainstay of treatment for many inflammatory conditions and is being evaluated for fibrotic disorders. The question of whether anti-cytokine therapy will prove useful for intestinal fibrosis is, therefore, acutely relevant. This review will highlight some of the current therapeutics targeting cytokines involved in fibrosis.
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Affiliation(s)
- Noam Jacob
- F. Widjaja Foundation, Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Division of Digestive Diseases, Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Stephan R Targan
- F. Widjaja Foundation, Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - David Q Shih
- F. Widjaja Foundation, Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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27
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Ferrari D, Gambari R, Idzko M, Müller T, Albanesi C, Pastore S, La Manna G, Robson SC, Cronstein B. Purinergic signaling in scarring. FASEB J 2016; 30:3-12. [PMID: 26333425 PMCID: PMC4684510 DOI: 10.1096/fj.15-274563] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 08/17/2015] [Indexed: 12/23/2022]
Abstract
Adenosine (ADO) and nucleotides such as ATP, ADP, and uridine 5'-triphosphate (UTP), among others, may serve as extracellular signaling molecules. These mediators activate specific cell-surface receptors-namely, purinergic 1 and 2 (P1 and P2)-to modulate crucial pathophysiological responses. Regulation of this process is maintained by nucleoside and nucleotide transporters, as well as the ectonucleotidases ectonucleoside triphosphate diphosphohydrolase [ENTPD; cluster of differentiation (CD)39] and ecto-5'-nucleotidase (5'-NT; CD73), among others. Cells involved in tissue repair, healing, and scarring respond to both ADO and ATP. Our recent investigations have shown that modulation of purinergic signaling regulates matrix deposition during tissue repair and fibrosis in several organs. Cells release adenine nucleotides into the extracellular space, where these mediators are converted by CD39 and CD73 into ADO, which is anti-inflammatory in the short term but may also promote dermal, heart, liver, and lung fibrosis with repetitive signaling under defined circumstances. Extracellular ATP stimulates cardiac fibroblast proliferation, lung inflammation, and fibrosis. P2Y2 (UTP/ATP) and P2Y6 [ADP/UTP/uridine 5'-diphosphate (UDP)] have been shown to have profibrotic effects, as well. Modulation of purinergic signaling represents a novel approach to preventing or diminishing fibrosis. We provide an overview of the current understanding of purinergic signaling in scarring and discuss its potential to prevent or decrease fibrosis.
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Affiliation(s)
- Davide Ferrari
- *Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA
| | - Roberto Gambari
- *Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA
| | - Marco Idzko
- *Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA
| | - Tobias Müller
- *Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA
| | - Cristina Albanesi
- *Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA
| | - Saveria Pastore
- *Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA
| | - Gaetano La Manna
- *Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA
| | - Simon C Robson
- *Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA
| | - Bruce Cronstein
- *Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Pneumology, University of Freiburg, Freiburg, Germany; Laboratory of Immunology and Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy; Department of Specialized, Diagnostic, and Experimental Medicine, University of Bologna, Bologna, Italy; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, USA; and Department of Medicine, New York University, New York, New York, USA
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Li Y, Stocchi L, Shen B, Liu X, Remzi FH. Salvage surgery after failure of endoscopic balloon dilatation versus surgery first for ileocolonic anastomotic stricture due to recurrent Crohn's disease. Br J Surg 2015; 102:1418-25; discussion 1425. [PMID: 26313750 DOI: 10.1002/bjs.9906] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 06/03/2015] [Accepted: 06/23/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND Both surgical resection and endoscopic balloon dilatation are treatment options for ileocolonic anastomotic stricture caused by recurrent Crohn's disease unresponsive to medications. Perioperative outcomes of salvage surgery owing to failed endoscopic balloon dilatation in comparison with performing surgery first for the same indication are unclear. METHODS An analysis of a prospectively maintained Crohn's disease database was carried out to compare perioperative outcomes of patients who had surgery for failure of endoscopic balloon dilatation with outcomes in patients who underwent resection first for ileocolonic anastomotic stricture caused by recurrent Crohn's disease between 1997 and 2013. RESULTS Of 194 patients, 114 (58·8 per cent) underwent surgery without previous endoscopic balloon dilatation. The remaining 80 patients had salvage surgery after one or more endoscopic balloon dilatations during a median treatment span of 14·5 months. Patients in the salvage surgery group had a significantly shorter length of anastomotic stricture (P < 0·001). Salvage surgery was associated with increased rates of stoma formation (P = 0·030), overall surgical-site infection (SSI) (P = 0·025) and organ/space SSI (P = 0·030). In multivariable analysis, preoperative endoscopic balloon dilatation was independently associated with both postoperative SSI (odds ratio 3·16, 95 per cent c.i. 1·01 to 9·84; P = 0·048) and stoma diversion (odds ratio 3·33, 1·14 to 9·78; P = 0·028). CONCLUSION Salvage surgery after failure of endoscopic balloon dilatation is associated with increased adverse outcomes in comparison with surgery first. This should be discussed with patients being considered for endoscopic balloon dilatation for ileocolonic anastomotic stricture due to recurrent Crohn's disease.
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Affiliation(s)
- Y Li
- Departments of Colorectal Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - L Stocchi
- Departments of Colorectal Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - B Shen
- Departments of Gastroenterology/Hepatology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - X Liu
- Departments of Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - F H Remzi
- Departments of Colorectal Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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Chang PY, Qu YQ, Wang J, Dong LH. The potential of mesenchymal stem cells in the management of radiation enteropathy. Cell Death Dis 2015; 6:e1840. [PMID: 26247725 PMCID: PMC4558492 DOI: 10.1038/cddis.2015.189] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Revised: 06/02/2015] [Accepted: 06/08/2015] [Indexed: 12/20/2022]
Abstract
Although radiotherapy is effective in managing abdominal and pelvic malignant tumors, radiation enteropathy is still unavoidable. This disease severely affects the quality of life of cancer patients due to some refractory lesions, such as intestinal ischemia, mucositis, ulcer, necrosis or even perforation. Current drugs or prevailing therapies are committed to alleviating the symptoms induced by above lesions. But the efficacies achieved by these interventions are still not satisfactory, because the milieus for tissue regeneration are not distinctly improved. In recent years, regenerative therapy for radiation enteropathy by using mesenchymal stem cells is of public interests. Relevant results of preclinical and clinical studies suggest that this regenerative therapy will become an attractive tool in managing radiation enteropathy, because mesenchymal stem cells exhibit their pro-regenerative potentials for healing the injuries in both epithelium and endothelium, minimizing inflammation and protecting irradiated intestine against fibrogenesis through activating intrinsic repair actions. In spite of these encouraging results, whether mesenchymal stem cells promote tumor growth is still an issue of debate. On this basis, we will discuss the advances in anticancer therapy by using mesenchymal stem cells in this review after analyzing the pathogenesis of radiation enteropathy, introducing the advances in managing radiation enteropathy using regenerative therapy and exploring the putative actions by which mesenchymal stem cells repair intestinal injuries. At last, insights gained from the potential risks of mesenchymal stem cell-based therapy for radiation enteropathy patients may provide clinicians with an improved awareness in carrying out their studies.
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Affiliation(s)
- P-Y Chang
- 1] Department of Radiation Oncology, The First Bethune Hospital of Jilin University, Changchun 130021, China [2] Electrochemical State Key Laboratory, Changchun Institute of Applied Chemistry Academy of Science, Changchun 130021, China
| | - Y-Q Qu
- Department of Radiation Oncology, The First Bethune Hospital of Jilin University, Changchun 130021, China
| | - J Wang
- Electrochemical State Key Laboratory, Changchun Institute of Applied Chemistry Academy of Science, Changchun 130021, China
| | - L-H Dong
- Department of Radiation Oncology, The First Bethune Hospital of Jilin University, Changchun 130021, China
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Latella G, Di Gregorio J, Flati V, Rieder F, Lawrance IC. Mechanisms of initiation and progression of intestinal fibrosis in IBD. Scand J Gastroenterol 2015; 50:53-65. [PMID: 25523556 DOI: 10.3109/00365521.2014.968863] [Citation(s) in RCA: 139] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Intestinal fibrosis is a common complication of the inflammatory bowel diseases (IBDs). It becomes clinically apparent in >30% of patients with Crohn's disease (CD) and in about 5% with ulcerative colitis (UC). Fibrosis is a consequence of local chronic inflammation and is characterized by excessive extracellular matrix (ECM) protein deposition. ECM is produced by activated myofibroblasts, which are modulated by both, profibrotic and antifibrotic factors. Fibrosis depends on the balance between the production and degradation of ECM proteins. This equilibrium can be impacted by a complex and dynamic interaction between profibrotic and antifibrotic mediators. Despite the major therapeutic advances in the treatment of active inflammation in IBD over the past two decades, the incidence of intestinal strictures in CD has not significantly changed as the current anti-inflammatory therapies neither prevent nor reverse the established fibrosis and strictures. This implies that control of intestinal inflammation does not necessarily affect the associated fibrotic process. The conventional view that intestinal fibrosis is an inevitable and irreversible process in patients with IBD is also gradually changing in light of an improved understanding of the cellular and molecular mechanisms that underline the pathogenesis of fibrosis. Comprehension of the mechanisms of intestinal fibrosis is thus vital and may pave the way for the developments of antifibrotic agents and new therapeutic approaches in IBD.
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Affiliation(s)
- Giovanni Latella
- Department of Life, Health and Environmental Sciences, Gastroenterology Unit, University of L'Aquila , L'Aquila , Italy
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Yoo JH, Ho S, Tran DHY, Cheng M, Bakirtzi K, Kubota Y, Ichikawa R, Su B, Tran DHN, Hing TC, Chang I, Shih DQ, Issacson RE, Gallo RL, Fiocchi C, Pothoulakis C, Koon HW. Anti-fibrogenic effects of the anti-microbial peptide cathelicidin in murine colitis-associated fibrosis. Cell Mol Gastroenterol Hepatol 2014; 1:55-74.e1. [PMID: 25729764 PMCID: PMC4338438 DOI: 10.1016/j.jcmgh.2014.08.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Cathelicidin (LL-37 in human and mCRAMP in mice) represents a family of endogenous antimicrobial peptides with anti-inflammatory effects. LL-37 also suppresses collagen synthesis, an important fibrotic response, in dermal fibroblasts. Here we determined whether exogenous cathelicidin administration modulates intestinal fibrosis in two animal models of intestinal inflammation and in human colonic fibroblasts. METHODS C57BL/6J mice (n=6 per group) were administered intracolonically with a trinitrobenzene sulphonic acid (TNBS) enema to induce chronic (6-7 weeks) colitis with fibrosis. mCRAMP peptide (5 mg/kg every 3 day, week 5-7) or cathelicidin gene (Camp)-expressing lentivirus (107 infectious units week 4) were administered intracolonically or intravenously, respectively. 129Sv/J mice were infected with Salmonella typhimurium orally to induce cecal inflammation with fibrosis. Camp expressing lentivirus (107 infectious units day 11) was administered intravenously. RESULTS TNBS-induced chronic colitis was associated with increased colonic collagen (col1a2) mRNA expression. Intracolonic cathelicidin (mCRAMP peptide) administration or intravenous delivery of lentivirus-overexpressing cathelicidin gene significantly reduced colonic col1a2 mRNA expression in TNBS-exposed mice, compared to vehicle administration. Salmonella infection also caused increased cecal inflammation associated with collagen (col1a2) mRNA expression that was prevented by intravenous delivery of Camp-expressing lentivirus. Exposure of human primary intestinal fibroblasts and human colonic CCD-18Co fibroblasts to transforming growth factor-beta1 (TGF-beta1) and/or insulin-like growth factor 1 induced collagen protein and mRNA expression, that was reduced by LL-37 (3-5 µM) through a MAP kinase-dependent mechanism. CONCLUSION Cathelicidin can reverse intestinal fibrosis by directly inhibiting collagen synthesis in colonic fibroblasts.
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Affiliation(s)
- Jun Hwan Yoo
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, California,Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, South Korea
| | - Samantha Ho
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, California
| | - Deanna Hoang-Yen Tran
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, California
| | - Michelle Cheng
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, California
| | - Kyriaki Bakirtzi
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, California
| | - Yuzu Kubota
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, California
| | - Ryan Ichikawa
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, California
| | - Bowei Su
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, California
| | - Diana Hoang-Ngoc Tran
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, California
| | - Tressia C. Hing
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, California
| | - Irene Chang
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, California
| | - David Q. Shih
- F. Widjaja Foundation, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Richard E. Issacson
- Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota
| | - Richard L. Gallo
- Division of Dermatology, University of California–San Diego, San Diego, California
| | - Claudio Fiocchi
- Department of Pathobiology, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Charalabos Pothoulakis
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, California
| | - Hon Wai Koon
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, California,Correspondence Address correspondence to: Hon Wai Koon, PhD, Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, MRL Building, Room 1519, 675 Charles E. Young Dr. South, Los Angeles, California 90095. fax: (310) 825-3542.
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Vidigal FM, de Souza GS, Chebli LA, da Rocha Ribeiro TC, Furtado MCV, Castro ACS, Pinto ALT, do Valle Pinheiro B, de Lima Pace FH, de Oliveira JM, de Oliveira Zanini KA, Gaburri PD, Zanini A, Ribeiro LC, Chebli JMF. Azathioprine is more effective than mesalazine at preventing recurrent bowel obstruction in patients with ileocecal Crohn's disease. Med Sci Monit 2014; 20:2165-2170. [PMID: 25370731 PMCID: PMC4301229 DOI: 10.12659/msm.890975] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 06/07/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Patients with subocclusive Crohn's disease (CD) who received azathioprine (AZA) therapy had lower re-hospitalization rates due to all causes and for surgical management of CD compared to those treated with mesalazine during a 3-year period. We investigated whether AZA also was effective for prevention of recurrent bowel obstruction. MATERIAL/METHODS Rates of recurrent bowel occlusion were compared between patients treated with AZA and those treated with mesalazine. We assessed the time interval-off intestinal obstruction as well as the occlusion-free survival for both groups. RESULTS There was a significantly lower cumulative rate of patients with recurrent subocclusion in the AZA group (56%) compared with the mesalazine group (79%; OR 3.34, 95% CI 1.67-8.6; P=0.003), with the number needed to treat in order to prevent 1 subocclusion episode of 3.7 favoring AZA. The occlusion-free time interval was longer in the AZA group compared with the mesalazine group (28.8 vs. 18.3 months; P=0.000). The occlusion-free survival at 12, 24, and 36 months was significantly higher in the AZA group (91%, 81%, and 72%, respectively) than in the mesalazine group (64.7%, 35.3%, and 23.5%, respectively; P<0.05 for all comparisons). CONCLUSIONS In an exploratory analysis of patients with subocclusive ileocecal CD, maintenance therapy with AZA is more effective than mesalazine for eliminating or postponing recurrent intestinal obstruction during 3 years of therapy.
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Affiliation(s)
- Fernando Mendonça Vidigal
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora, Minas Gerais, Brazil
- Division of Surgery, Santa Casa de Misericordia, Juiz de Fora, Minas Gerais, Brazil
| | - Gláucio Silva de Souza
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora, Minas Gerais, Brazil
- Division of Surgery, Santa Casa de Misericordia, Juiz de Fora, Minas Gerais, Brazil
| | - Liliana Andrade Chebli
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora, Minas Gerais, Brazil
| | - Tarsila Campanha da Rocha Ribeiro
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora, Minas Gerais, Brazil
| | - Maria Cristina Vasconcellos Furtado
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora, Minas Gerais, Brazil
| | - Antonio Carlos Santana Castro
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora, Minas Gerais, Brazil
| | - André Luis Tavares Pinto
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora, Minas Gerais, Brazil
| | - Bruno do Valle Pinheiro
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora, Minas Gerais, Brazil
| | - Fabio Heleno de Lima Pace
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora, Minas Gerais, Brazil
| | - Juliano Machado de Oliveira
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora, Minas Gerais, Brazil
| | - Karine Andrade de Oliveira Zanini
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora, Minas Gerais, Brazil
| | - Pedro Duarte Gaburri
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora, Minas Gerais, Brazil
| | - Alexandre Zanini
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora, Minas Gerais, Brazil
| | - Luiz Cláudio Ribeiro
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora, Minas Gerais, Brazil
| | - Julio Maria Fonseca Chebli
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Diseases Center, University Hospital of the Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora, Minas Gerais, Brazil
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Bettenworth D, Rieder F. Medical therapy of stricturing Crohn's disease: what the gut can learn from other organs - a systematic review. FIBROGENESIS & TISSUE REPAIR 2014; 7:5. [PMID: 24678903 PMCID: PMC4230721 DOI: 10.1186/1755-1536-7-5] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 03/06/2014] [Indexed: 12/11/2022]
Abstract
Crohn’s disease (CD) is a chronic remitting and relapsing disease. Fibrostenosing complications such as intestinal strictures, stenosis and ultimately obstruction are some of its most common long-term complications. Despite recent advances in the pathophysiological understanding of CD and a significant improvement of anti-inflammatory therapeutics, medical therapy for stricturing CD is still inadequate. No specific anti-fibrotic therapy exists and the incidence rate of strictures has essentially remained unchanged. Therefore, the current therapy of established fibrotic strictures comprises mainly endoscopic dilation as well as surgical approaches. However, these treatment options are associated with major complications as well as high recurrence rates. Thus, a specific anti-fibrotic therapy for CD is urgently needed. Importantly, there is now a growing body of evidence for prevention as well as effective medical treatment of fibrotic diseases of other organs such as the skin, lung, kidney and liver. In face of the similarity of molecular mechanisms of fibrogenesis across these organs, translation of therapeutic approaches from other fibrotic diseases to the intestine appears to be a promising treatment strategy. In particular transforming growth factor beta (TGF-β) neutralization, selective tyrosine kinase inhibitors, blockade of components of the renin-angiotensin system, IL-13 inhibitors and mammalian target of rapamycin (mTOR) inhibitors have emerged as potential drug candidates for anti-fibrotic therapy and may retard progression or even reverse established intestinal fibrosis. However, major challenges have to be overcome in the translation of novel anti-fibrotics into intestinal fibrosis therapy, such as the development of appropriate biomarkers that predict the development and accurately monitor therapeutic responses. Future clinical studies are a prerequisite to evaluate the optimal timing for anti-fibrotic treatment approaches, to elucidate the best routes of application, and to evaluate the potential of drug candidates to reach the ultimate goal: the prevention or reversal of established fibrosis and strictures in CD patients.
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Affiliation(s)
| | - Florian Rieder
- Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.,Department of Pathobiology, Lerner Research Institute, NC22, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
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Quencer KB, Nimkin K, Mino-Kenudson M, Gee MS. Detecting active inflammation and fibrosis in pediatric Crohn's disease: prospective evaluation of MR-E and CT-E. ACTA ACUST UNITED AC 2013; 38:705-13. [PMID: 23361877 DOI: 10.1007/s00261-013-9981-z] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Symptoms of Crohn's disease (CD) can be due to active inflammation or fibrosis. Differentiating these based on clinical presentation, endoscopy, laboratory parameters, and clinical scoring methods can be inaccurate and/or invasive. As therapy decisions are often directed based on whether active disease or fibrosis is present, a reliable and non-invasive test to distinguish these two etiologies would be a powerful clinical tool. CT enterography (CT-E) and MR enterography (MR-E) are two non-invasive imaging modalities tailored to evaluate the small bowel. The purpose of our study was to compare the ability of MR-E and CT-E to assess for active inflammation and mural fibrosis in patients with known CD as compared to a histologic reference standard. After obtaining MR-E and CT-E on the same day, a total of 61 histologic samples were obtained from twelve subjects aged 12-20 years via full-thickness bowel resection or endoscopy. These were evaluated by the pathologist for active inflammation and fibrosis. We found that while CT-E and MR-E were similar in their accuracies of depicting active inflammation, MR-E was significantly more sensitive in detecting fibrosis. Because of this and the lack of ionizing radiation from MR-E, we believe that MR-E rather than CT-E should serve as the primary imaging modality for the assessment of CD pediatric patients with non-acute clinical exacerbations.
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Affiliation(s)
- Keith B Quencer
- Massachusetts General Hospital/Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
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Latella G, Papi C. Crucial steps in the natural history of inflammatory bowel disease. World J Gastroenterol 2012; 18:3790-9. [PMID: 22876029 PMCID: PMC3413049 DOI: 10.3748/wjg.v18.i29.3790] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2012] [Revised: 04/18/2012] [Accepted: 05/05/2012] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic, progressive and disabling disorders. Over the last few decades, new therapeutic approaches have been introduced which have led not only to a reduction in the mortality rate but also offered the possibility of a favorable modification in the natural history of IBD. The identification of clinical, genetic and serological prognostic factors has permitted a better stratification of the disease, thus allowing the opportunity to indicate the most appropriate therapy. Early treatment with immunosuppressive drugs and biologics has offered the opportunity to change, at least in the short term, the course of the disease by reducing, in a subset of patients with IBD, hospitalization and the need for surgery. In this review, the crucial steps in the natural history of both UC and CD will be discussed, as well as the factors that may change their clinical course. The methodological requirements for high quality studies on the course and prognosis of IBD, the true impact of environmental and dietary factors on the clinical course of IBD, the clinical, serological and genetic predictors of the IBD course (in particular, which of these are relevant and appropriate for use in clinical practice), the impact of the various forms of medical treatment on the IBD complication rate, the role of surgery for IBD in the biologic era, the true magnitude of risk of colorectal cancer associated with IBD, as well as the mortality rate related to IBD will be stressed; all topics that are extensively discussed in separate reviews included in this issue of World Journal of Gastroenterology.
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Sipos F, Valcz G, Molnár B. Physiological and pathological role of local and immigrating colonic stem cells. World J Gastroenterol 2012; 18:295-301. [PMID: 22294835 PMCID: PMC3261524 DOI: 10.3748/wjg.v18.i4.295] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2011] [Revised: 06/27/2011] [Accepted: 07/04/2011] [Indexed: 02/06/2023] Open
Abstract
The latest avenue of research is revealing the existence of and role for the colonic stem cells in the physiological renewal of the mucosa and in pathological circumstances where they have both positive and negative effects. In the case of human colon, different levels of stem cell compartments exist. First, the crypt epithelial stem cells, which have a role in the normal crypt epithelial cell dynamics and in colorectal carcinogenesis. Close to the crypts, the second layer of stem cells can be found; the local subepithelial stem cell niche, including the pericryptic subepithelial myofibroblasts that regulate the epithelial cell differentiation and have a crucial role in cancer progression and chronic inflammation-related fibrosis. The third level of stem cell compartment is the immigrating bone-marrow-derived stem cells, which have an important role in wound healing after severe mucosal inflammation, but are also involved in cancer invasion. This paper focuses on stem cell biology in the context of physiological and pathological processes in the human colon.
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Affiliation(s)
- Ferenc Sipos
- Ferenc Sipos, Gábor Valcz, 2nd Department of Internal Medicine, Semmelweis University, 1088 Budapest, Hungary.
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Latella G, Caprilli R, Travis S. In favour of early surgery in Crohn's disease: a hypothesis to be tested. J Crohns Colitis 2011; 5:1-4. [PMID: 21272796 DOI: 10.1016/j.crohns.2010.11.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2010] [Accepted: 11/11/2010] [Indexed: 02/08/2023]
Affiliation(s)
- Giovanni Latella
- Department of Internal Medicine, Gastroenterology Unit, University of L'Aquila, Piazza S. Tomamsi, 1-Coppito, 67100 L'Aquila, Italy.
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Ren Y, Zhang C, An C, Wu H, Hong J, Wu L, Liu J, Ma X. Effects of herb-partitioned moxibustion and electroacupuncture on serum indexes of intestinal fibrosis in rats with Crohn’s disease. JOURNAL OF ACUPUNCTURE AND TUINA SCIENCE 2011. [DOI: 10.1007/s11726-011-0460-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Sahni VA, Shyn PB. Predicting the need for surgery in obstructive Crohn's disease: how hot is PET/CT? Inflamm Bowel Dis 2010; 16:2182-3. [PMID: 20848519 DOI: 10.1002/ibd.21335] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Affiliation(s)
- V Anik Sahni
- Division of Abdominal Imaging and Intervention, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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