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Xu S, Yue H, Zhang T, Zhou Z, Wang B, Ou Y, Deng S, Yin J, Zheng S. Parental high-fat diet induces upregulation of macrophage receptor with collagenous structure expression and exacerbates colorectal inflammation via the nuclear factor kappa-B pathway in offspring. J Nutr Biochem 2025; 142:109918. [PMID: 40254038 DOI: 10.1016/j.jnutbio.2025.109918] [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: 12/15/2024] [Revised: 03/20/2025] [Accepted: 04/04/2025] [Indexed: 04/22/2025]
Abstract
Parental high-fat diet (HFD) increases offspring's susceptibility to colorectal inflammation, but the underlying mechanism remains unclear. Using mouse models, we compared colorectal inflammation between offspring of HFD-fed and normal diet-fed parents. Histological analysis and immunostaining revealed that offspring of HFD-fed parents exhibited shortened colorectal length, decreased goblet cells, and reduced tight junction protein expression, particularly when maintained on HFD. RNA sequencing of colorectal tissue identified elevated expression of macrophage receptor with collagenous structure (MARCO) in these offspring. Immunofluorescence co-localization staining confirmed increased MARCO-positive macrophages in their colorectal tissue. Notably, switching offspring to normal diet partially alleviated these inflammatory responses, although some manifestations remained. Further investigation showed that high-lipid stimulation increased MARCO expression in macrophages and promoted inflammatory cytokine secretion through nuclear factor kappa-B (NF-κB) pathway activation. In vitro experiments demonstrated that MARCO knockdown inhibited the expression of inflammatory cytokines and prevented tight junction protein destruction in cocultured intestinal cells. Our findings reveal that parental HFD induces MARCO upregulation in offspring's colorectal macrophages and exacerbates colorectal inflammation through the NF-κB pathway, providing new insights into the mechanism by which parental HFD affects offspring's intestinal health.
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Affiliation(s)
- Shenghao Xu
- Department of Gastroenterology and Hepatology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Hui Yue
- Department of Gastroenterology and Hepatology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Ting Zhang
- Department of Gastroenterology and Hepatology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Zhirui Zhou
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China; Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Bingbing Wang
- Department of Gastroenterology and Hepatology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yinhua Ou
- Department of Gastroenterology and Hepatology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Sanhua Deng
- Department of Gastroenterology and Hepatology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Jianbin Yin
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangzhou, China; Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; Department of Joint Surgery, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
| | - Shimin Zheng
- Department of Gastroenterology and Hepatology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China; The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China; Department of Rheumatology and Immunology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
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Oprysk LM, Vazquez M, Shinbrot T. Internal cohesion gradient as a novel mechanism of collective cell migration. PLoS Comput Biol 2025; 21:e1012769. [PMID: 40063623 PMCID: PMC12077783 DOI: 10.1371/journal.pcbi.1012769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 05/14/2025] [Accepted: 01/07/2025] [Indexed: 05/16/2025] Open
Abstract
Experiments demonstrate that individual cells that wander stochastically can migrate persistently as a cluster. We show by simulating cells and their interactions that collective migration by omnidirectional cells is a generic phenomenon that can be expected to arise whenever (a) leading and trailing cells migrate randomly, and (b) leading cells are more closely packed than trailing neighbors. The first condition implies that noise is essential to cluster motion, while the second implies that an internal cohesion gradient can drive external motion of a cluster. Unlike other swarming phenomena, we find that this effect is driven by cohesion asymmetry near the leading cell, and motion of interior cells contribute minimally - and in fact interfere with - a cluster's persistent migration.
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Affiliation(s)
- Larissa M. Oprysk
- Department of Biomedical Engineering Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America
| | - Maribel Vazquez
- Department of Biomedical Engineering Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America
| | - Troy Shinbrot
- Department of Biomedical Engineering Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America
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Wang Y, Ji X, Wang X, Sun M, Li C, Wu D. Cannabidiol Alleviates Intestinal Fibrosis in Mice with Ulcerative Colitis by Regulating Transforming Growth Factor Signaling Pathway. J Inflamm Res 2025; 18:1-15. [PMID: 39802511 PMCID: PMC11717655 DOI: 10.2147/jir.s485007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 11/12/2024] [Indexed: 01/16/2025] Open
Abstract
Objective The aim of this study is to investigate the protective effect of Cannabidiol (CBD) on DSS-induced colitis in C57BL/6 mice and its related pathways. Methods A mouse model of ulcerative colitis (US) was induced by DSS. Enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription polymerase-chain reaction (qRT-PCR), Western blot (WB) and immunofluorescence (IF) were used to identify the key factors involved in inflammatory response, oxidative stress and intestinal fibrosis. In addition, we transfected si-RNA into CCD-18Co cells. Results The research suggests that CBD significantly improves intestinal inflammation by up-regulating the nuclear factor erythroid 2-related factor 2 (Nrf2) expression, inhibiting the classical Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κb) pathway, and inhibiting the release of IL-6 (Interleukin), IL-1β, Tumor Necrosis Factor-α (TNF-α) and other factors. At the same time, CBD plays an antioxidant role by regulating Nrf2/ HO-1 (Heme Oxygenase-1) pathway and activating HO-1 activity. On the other hand, CBD may regulate Transforming growth factor beta (TGF-β)/SMADs signaling pathway by inhibiting the expression of TGF-β1, thereby inhibiting the expression of α-SMA, Collagen1, TIMP1 and other factors, thus playing an anti-fibrotic role. Notably, when Nrf2 is inhibited or lacking, CBD loses the above protective effect against DSS-induced colon injury. Conclusion CBD affects the classical NF-κb pathway, Nrf2/ Heme Oxygenase-1 (HO-1) pathway, and Transforming growth factor beta (TGF-β)/SMAD pathway by regulating Nrf2, thereby reducing colonic inflammation and oxidative stress and improving the progression of colonic fibrosis.
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Affiliation(s)
- Ye Wang
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases School of Basic Medicine, Jiamusi University, Jiamusi, People’s Republic of China
- Department of Gastroenterology, Tianjin First Central Hospital, Tianjin, People’s Republic of China
| | - Xingming Ji
- Department of Gastroenterology, Tianjin First Central Hospital, Tianjin, People’s Republic of China
- School of Medicine, Nankai University, Tianjin, People’s Republic of China
| | - Xinyi Wang
- Department of Gastroenterology, Tianjin First Central Hospital, Tianjin, People’s Republic of China
| | - Mengyu Sun
- Department of Gastroenterology, Tianjin First Central Hospital, Tianjin, People’s Republic of China
| | - Cheng Li
- Department of Gastroenterology, Tianjin First Central Hospital, Tianjin, People’s Republic of China
- School of Medicine, Nankai University, Tianjin, People’s Republic of China
| | - Dongmei Wu
- School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, People’s Republic of China
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Jun YK, Kim N, Yoon H, Park JH, Kim HK, Choi Y, Lee JA, Shin CM, Park YS, Lee DH. Molecular Activity of Inflammation and Epithelial-Mesenchymal Transition in the Microenvironment of Ulcerative Colitis. Gut Liver 2024; 18:1037-1047. [PMID: 38384179 PMCID: PMC11565011 DOI: 10.5009/gnl230283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 12/07/2023] [Accepted: 12/20/2023] [Indexed: 02/23/2024] Open
Abstract
Background/Aims : The genetic expression in the active inflammatory regions is increased in ulcerative colitis (UC) with endoscopic activity. The aim of this study was to investigate the molecular activity of inflammation and tissue remodeling markers in endoscopically inflamed and uninflamed regions of UC. Methods : Patients with UC (n=47) and controls (n=20) were prospectively enrolled at the Seoul National University Bundang Hospital. Inflamed tissue was obtained at the most active lesion, and uninflamed tissue was collected from approximately 15 cm above the upper end of the active lesion via colonoscopic biopsies. The messenger RNA expression levels of transforming growth factor β (TGF-β), interleukin (IL)-1β, IL-6, IL-17A, E-cadherin, olfactomedin-4 (OLFM4), leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), vimentin, fibroblast-specific protein-1 (FSP1), and α-smooth muscle actin (SMA) were evaluated. Mucosal healing (MH) was defined according to a Mayo endoscopic score of 0, 1 or non-MH (Mayo endoscopic score of 2 or 3). Results : The messenger RNA expressions of TGF-β, IL-1β, OLFM4, FSP1, vimentin, and α-SMA were significantly higher, and that of E-cadherin was significantly lower in inflamed and uninflamed regions of patients with UC than those in controls. In the inflamed regions, patients in the non-MH group had significantly increased genetic expression of TGF-β, FSP1, vimentin, and α-SMA compared to patients in the MH group. Similarly, the non-MH group had significantly higher genetic expression of TGF-β, IL-1β, IL-6, vimentin, and α-SMA than the MH group in the uninflamed regions. Conclusions : Endoscopic activity in UC suggests inflammation and tissue remodeling of uninflamed regions similar to inflamed regions (ClinicalTrials.gov, NCT05653011).
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Affiliation(s)
- Yu Kyung Jun
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ji Hyun Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyung Kyung Kim
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Pathology and Translational Genomics, Samsung Medical Center, Seoul, Korea
| | - Yonghoon Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ji Ae Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Young Soo Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Rieder F, Ma C, Hanzel J, Fletcher JG, Baker ME, Wang Z, Guizzetti L, Shackelton LM, Rémillard J, Patel M, Niu J, Ottichilo R, Santillan CS, Capozzi N, Taylor SA, Bruining DH, Zou G, Feagan BG, Jairath V, Rimola J, Atzen S. Reliability of CT Enterography for Describing Fibrostenosing Crohn Disease. Radiology 2024; 312:e233038. [PMID: 39105638 PMCID: PMC11366669 DOI: 10.1148/radiol.233038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 04/12/2024] [Accepted: 04/23/2024] [Indexed: 08/07/2024]
Abstract
Background Standardized methods to measure and describe Crohn disease strictures at CT enterography are needed to guide clinical decision making and for use in therapeutic studies. Purpose To assess the reliability of CT enterography features to describe Crohn disease strictures and their correlation with stricture severity. Materials and Methods A retrospective study was conducted in 43 adult patients with symptomatic terminal ileal Crohn disease strictures who underwent standard-of-care CT enterography at a tertiary care center at the Cleveland Clinic between January 2008 and August 2016. After training on standardized definitions, four abdominal radiologists blinded to all patient information assessed imaging features (seven continuous measurements and nine observations) of the most distal ileal stricture in two separate sessions (separated by ≥2 weeks) in random order. Features with an interrater intraclass correlation coefficient (ICC) of 0.41 or greater (ie, moderate reliability or better) were considered reliable. Univariable and multivariable linear regression analysis identified reliable features associated with a visual analog scale of overall stricture severity. Significant reliable features were assessed as components of a CT enterography-based model to quantitate stricture severity. Results Examinations in 43 patients (mean age, 52 years ± 16 [SD]; 23 female) were evaluated. Five continuous measurements and six observations demonstrated at least moderate interrater reliability (interrater ICC range, 0.42 [95% CI: 0.25, 0.57] to 0.80 [95% CI: 0.67, 0.88]). Of these, 10 were univariably associated with stricture severity, and three continuous measurements-stricture length (interrater ICC, 0.64 [95% CI: 0.42, 0.81]), maximal associated small bowel dilation (interrater ICC, 0.80 [95% CI: 0.67, 0.88]), and maximal stricture wall thickness (interrater ICC, 0.50 [95% CI: 0.34, 0.62])-were independently associated (P value range, <.001 to .003) with stricture severity in a multivariable model. These three measurements were used to derive a well-calibrated (optimism-adjusted calibration slope = 1.00) quantitative model of stricture severity. Conclusion Standardized CT enterography measurements and observations can reliably describe terminal ileal Crohn disease strictures. Stricture length, maximal associated small bowel dilation, and maximal stricture wall thickness are correlated with stricture severity. © RSNA, 2024 Supplemental material is available for this article. See also the article by Rieder et al in this issue. See also the editorial by Galgano and Summerlin in this issue.
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Affiliation(s)
| | | | - Jurij Hanzel
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - Joel G. Fletcher
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - Mark E. Baker
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - Zhongya Wang
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - Leonardo Guizzetti
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - Lisa M. Shackelton
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - Julie Rémillard
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - Mihir Patel
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - Jiafei Niu
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - Ronald Ottichilo
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - Cynthia S. Santillan
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - Nunzia Capozzi
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - Stuart A. Taylor
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - David H. Bruining
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - Guangyong Zou
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - Brian G. Feagan
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | | | | | - for the Stenosis Therapy and Anti-Fibrotic Research (STAR)
Consortium
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
| | - Sarah Atzen
- From the Department of Inflammation and Immunity, Lerner Research
Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195 (F.R.);
Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases
and Surgery Institute and Program for Global Translational Inflammatory Bowel
Diseases Research, Cleveland Clinic, Cleveland, Ohio (F.R., M.P., J.N., R.O.);
Departments of Medicine and Community Health Sciences, Division of
Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
(C.M.); Alimentiv, London, Ontario, Canada (C.M., J.H., Z.W., L.G., L.M.S., J.
Rémillard, G.Z., B.G.F., V.J.); Department of Gastroenterology,
University of Ljubljana, University Medical Centre Ljubljana, Ljubljana,
Slovenia (J.H.); Department of Radiology, Mayo Clinic, Rochester, Minn (J.G.F.);
Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery
Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
(M.E.B.); Department of Radiology, University of California San Diego, San
Diego, Calif (C.S.S.); Department of Radiology, IBD Unit, Hospital Clínic
de Barcelona, Barcelona, Spain (N.C., J. Rimola); Pediatric and Adult
Cardiothoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS
Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (N.C.); Centre for
Medical Imaging, University College London, London, England (S.A.T.); Division
of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science,
Rochester, Minn (D.H.B.); and Departments of Medicine and Epidemiology and
Biostatistics, Schulich School of Medicine and Dentistry, University of Western
Ontario, London, Ontario, Canada (B.G.F., V.J.)
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6
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Zhang M, Zeng Y, Fang ZN, Wang YD, Zhang RN, Ye Z, Cao QH, Mao R, Sun C, Chen ZH, Huang B, Li XH. MRI radiomics enhances radiologists' ability for characterizing intestinal fibrosis in patients with Crohn's disease. Insights Imaging 2024; 15:165. [PMID: 38940988 PMCID: PMC11213838 DOI: 10.1186/s13244-024-01740-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 06/09/2024] [Indexed: 06/29/2024] Open
Abstract
OBJECTIVES We aimed to develop MRI-based radiomic models (RMs) to improve the diagnostic accuracy of radiologists in characterizing intestinal fibrosis in patients with Crohn's disease (CD). METHODS This retrospective study included patients with refractory CD who underwent MR before surgery from November 2013 to September 2021. Resected bowel segments were histologically classified as none-mild or moderate-severe fibrosis. RMs based on different MR sequence combinations (RM1: T2WI and enhanced-T1WI; RM2: T2WI, enhanced-T1WI, diffusion-weighted imaging [DWI], and apparent diffusion coefficient [ADC]); RM3: T2WI, enhanced-T1WI, DWI, ADC, and magnetization transfer MRI [MTI]), were developed and validated in an independent test cohort. The RMs' diagnostic performance was compared to that of visual interpretation using identical sequences and a clinical model. RESULTS The final population included 123 patients (81 men, 42 women; mean age: 30.26 ± 7.98 years; training cohort, n = 93; test cohort, n = 30). The area under the receiver operating characteristic curve (AUC) of RM1, RM2, and RM3 was 0.86 (p = 0.001), 0.88 (p = 0.001), and 0.93 (p = 0.02), respectively. The decision curve analysis confirmed a progressive improvement in the diagnostic performance of three RMs with the addition of more specific sequences. All RMs performance surpassed the visual interpretation based on the same MR sequences (visual model 1, AUC = 0.65, p = 0.56; visual model 2, AUC = 0.63, p = 0.04; visual model 3, AUC = 0.77, p = 0.002), as well as the clinical model composed of C-reactive protein and erythrocyte sedimentation rate (AUC = 0.60, p = 0.13). CONCLUSIONS The RMs, utilizing various combinations of conventional, DWI and MTI sequences, significantly enhance radiologists' ability to accurately characterize intestinal fibrosis in patients with CD. CRITICAL RELEVANCE STATEMENT The utilization of MRI-based RMs significantly enhances the diagnostic accuracy of radiologists in characterizing intestinal fibrosis. KEY POINTS MRI-based RMs can characterize CD intestinal fibrosis using conventional, diffusion, and MTI sequences. The RMs achieved AUCs of 0.86-0.93 for assessing fibrosis grade. MRI-radiomics outperformed visual interpretation for grading CD intestinal fibrosis.
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Affiliation(s)
- Mengchen Zhang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Yinghou Zeng
- Medical AI Lab, School of Biomedical Engineering, Medical School, Shenzhen University, Shenzhen, People's Republic of China
| | - Zhuang-Nian Fang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Yang-di Wang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Ruo-Nan Zhang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Ziyin Ye
- Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Qing-Hua Cao
- Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Canhui Sun
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Zhi-Hui Chen
- Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
| | - Bingsheng Huang
- Medical AI Lab, School of Biomedical Engineering, Medical School, Shenzhen University, Shenzhen, People's Republic of China.
| | - Xue-Hua Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
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Daulagala AC, Cetin M, Nair-Menon J, Jimenez DW, Bridges MC, Bradshaw AD, Sahin O, Kourtidis A. The epithelial adherens junction component PLEKHA7 regulates ECM remodeling and cell behavior through miRNA-mediated regulation of MMP1 and LOX. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.28.596237. [PMID: 38853930 PMCID: PMC11160653 DOI: 10.1101/2024.05.28.596237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
Epithelial adherens junctions (AJs) are cell-cell adhesion complexes that are influenced by tissue mechanics, such as those emanating from the extracellular matrix (ECM). Here, we introduce a mechanism whereby epithelial AJs can also regulate the ECM. We show that the AJ component PLEKHA7 regulates levels and activity of the key ECM remodeling components MMP1 and LOX in well-differentiated colon epithelial cells, through the miR-24 and miR-30c miRNAs. PLEKHA7 depletion in epithelial cells results in LOX-dependent ECM remodeling in culture and in the colonic mucosal lamina propria in mice. Furthermore, PLEKHA7-depleted cells exhibit increased migration and invasion rates that are MMP1- and LOX- dependent, and form colonies in 3D cultures that are larger in size and acquire aberrant morphologies in stiffer matrices. These results reveal an AJ-mediated mechanism, through which epithelial cells drive ECM remodeling to modulate their behavior, including acquisition of phenotypes that are hallmarks of conditions such as fibrosis and tumorigenesis.
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Affiliation(s)
- Amanda C. Daulagala
- Department of Regenerative Medicine and Cell Biology, Medical University South Carolina, Charleston, SC
| | - Metin Cetin
- Department of Biochemistry and Molecular Biology, Medical University South Carolina, Charleston, SC
| | - Joyce Nair-Menon
- Department of Regenerative Medicine and Cell Biology, Medical University South Carolina, Charleston, SC
| | - Douglas W. Jimenez
- Department of Regenerative Medicine and Cell Biology, Medical University South Carolina, Charleston, SC
| | - Mary Catherine Bridges
- Department of Regenerative Medicine and Cell Biology, Medical University South Carolina, Charleston, SC
| | - Amy D. Bradshaw
- Department of Medicine, Medical University South Carolina, Charleston, SC
| | - Ozgur Sahin
- Department of Biochemistry and Molecular Biology, Medical University South Carolina, Charleston, SC
| | - Antonis Kourtidis
- Department of Regenerative Medicine and Cell Biology, Medical University South Carolina, Charleston, SC
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8
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Ahmad S, Sands M, Greenberg E, Tangen L, Huang J, Irudayaraj JMK. Mucosal DNA methylome alteration in Crohn's disease: surgical and non-surgical groups. Front Genet 2023; 14:1244513. [PMID: 38046046 PMCID: PMC10691104 DOI: 10.3389/fgene.2023.1244513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 11/09/2023] [Indexed: 12/05/2023] Open
Abstract
Crohn's disease (CD) is characterized as a chronic, relapsing, and progressive disorder with a complex etiology involving interactions between host, microbiome, and the external environment. Genome wide association studies (GWAS) suggest several genetic variations in the diseased individuals but that explains only a small proportion of susceptibility to disease conditions. This indicates the possible role of epigenome which links environmental factors to the genetic variation in the disease etiology. The current study is focused on the DNA methylome evolution with disease progression. We performed Reduced Representation Bisulfite Sequencing (RRBS) to analyze differential DNA methylation in the diseased and healthy mucosal tissues of 2 different groups of CD patients: non-surgical and surgical, categorized based on the severity of disease and standard of care needed. Patients in both groups have unique DNA methylation signature compared to the healthy tissue. After removing single nucleotide polymorphisms (SNPs), 1,671 differentially methylated loci were found in the non-surgical and 3,334 in the surgical group of which only 206 were found overlapping in both groups. Furthermore, differential DNA methylation was noted in some of the GWAS associated genes implicated in CD. Also, functional enrichment analysis showed high representation of several key pathways where differential methylations were observed, and these can be implicated in CD pathogenesis. We identified specific DNA methylation patterns in the mucosal DNA of surgical and non-surgical CD patients which indicates evolution of the methylome as the disease progresses from initial to the advance stage. These unique patterns can be used as DNA methylation signatures to identify different stages of the disease.
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Affiliation(s)
- Saeed Ahmad
- Biomedical Research Center, Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, IL, United States
- Department of Bioengineering, University of Illinois Urbana-Champaign, Champaign, IL, United States
| | - Mia Sands
- Biomedical Research Center, Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, IL, United States
- Department of Bioengineering, University of Illinois Urbana-Champaign, Champaign, IL, United States
| | - Eugene Greenberg
- Digestive Health Institute, Carle Foundation Hospital, Urbana, IL, United States
| | - Lyn Tangen
- Digestive Health Institute, Carle Foundation Hospital, Urbana, IL, United States
| | - Jiacheng Huang
- Biomedical Research Center, Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, IL, United States
- Department of Bioengineering, University of Illinois Urbana-Champaign, Champaign, IL, United States
| | - Joseph Maria Kumar Irudayaraj
- Biomedical Research Center, Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, IL, United States
- Department of Bioengineering, University of Illinois Urbana-Champaign, Champaign, IL, United States
- Carl Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Champaign, IL, United States
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Champaign, IL, United States
- Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, Champaign, IL, United States
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9
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Jarmakiewicz-Czaja S, Sokal A, Ferenc K, Motyka E, Helma K, Filip R. The Role of Genetic and Epigenetic Regulation in Intestinal Fibrosis in Inflammatory Bowel Disease: A Descending Process or a Programmed Consequence? Genes (Basel) 2023; 14:1167. [PMID: 37372347 DOI: 10.3390/genes14061167] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 05/24/2023] [Accepted: 05/26/2023] [Indexed: 06/29/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are a group of chronic diseases characterized by recurring periods of exacerbation and remission. Fibrosis of the intestine is one of the most common complications of IBD. Based on current analyses, it is evident that genetic factors and mechanisms, as well as epigenetic factors, play a role in the induction and progression of intestinal fibrosis in IBD. Key genetic factors and mechanisms that appear to be significant include NOD2, TGF-β, TLRs, Il23R, and ATG16L1. Deoxyribonucleic acid (DNA) methylation, histone modification, and ribonucleic acid (RNA) interference are the primary epigenetic mechanisms. Genetic and epigenetic mechanisms, which seem to be important in the pathophysiology and progression of IBD, may potentially be used in targeted therapy in the future. Therefore, the aim of this study was to gather and discuss selected mechanisms and genetic factors, as well as epigenetic factors.
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Affiliation(s)
| | - Aneta Sokal
- Institute of Health Sciences, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
| | - Katarzyna Ferenc
- Institute of Medicine, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
| | - Elżbieta Motyka
- Centre for Innovative Research in Medical and Natural Sciences, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
| | - Kacper Helma
- Institute of Health Sciences, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
| | - Rafał Filip
- Institute of Medicine, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
- Department of Gastroenterology with IBD, Clinical Hospital No. 2 im. Św. Jadwigi Królowej, 35-301 Rzeszow, Poland
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10
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Pompili S, Vetuschi A, Latella G, Smakaj A, Sferra R, Cappariello A. PPAR-Gamma Orchestrates EMT, AGE, and Cellular Senescence Pathways in Colonic Epithelium and Restrains the Progression of IBDs. Int J Mol Sci 2023; 24:ijms24108952. [PMID: 37240299 DOI: 10.3390/ijms24108952] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/09/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023] Open
Abstract
Intestinal fibrosis, the most common complication of inflammatory bowel disease (IBD), is characterized by an uncontrolled deposition of extracellular matrix proteins leading to complications resolvable only with surgery. Transforming growth factor is the key player in the epithelial-mesenchymal transition (EMT) and fibrogenesis process, and some molecules modulating its activity, including peroxisome proliferator-activated receptor (PPAR)-γ and its agonists, exert a promising antifibrotic action. The purpose of this study is to evaluate the contribution of signaling other than EMT, such as the AGE/RAGE (advanced glycation end products/receptor of AGEs) and the senescence pathways, in the etiopathogenesis of IBD. We used human biopsies from control and IBD patients, and we used a mouse model of colitis induced by dextran-sodium-sulfate (DSS), without/with treatments with GED (PPAR-gamma-agonist), or 5-aminosalicylic acid (5-ASA), a reference drug for IBD treatment. In patients, we found an increase in EMT markers, AGE/RAGE, and senescence signaling activation compared to controls. Consistently, we found the overexpression of the same pathways in DSS-treated mice. Surprisingly, the GED reduced all the pro-fibrotic pathways, in some circumstances more efficiently than 5-ASA. Results suggest that IBD patients could benefit from a combined pharmacological treatment targeting simultaneously different pathways involved in pro-fibrotic signals. In this scenario, PPAR-gamma activation could be a suitable strategy to alleviate the signs and symptoms of IBD and also its progression.
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Affiliation(s)
- Simona Pompili
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy
| | - Antonella Vetuschi
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy
| | - Giovanni Latella
- Department of Life, Health, and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy
| | - Amarildo Smakaj
- Department of Geriatrics and Ortopaedic Sciences, University Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Roberta Sferra
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy
| | - Alfredo Cappariello
- Department of Life, Health, and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy
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11
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Cao Y, Cheng K, Yang M, Deng Z, Ma Y, Yan X, Zhang Y, Jia Z, Wang J, Tu K, Liang J, Zhang M. Orally administration of cerium oxide nanozyme for computed tomography imaging and anti-inflammatory/anti-fibrotic therapy of inflammatory bowel disease. J Nanobiotechnology 2023; 21:21. [PMID: 36658555 PMCID: PMC9854161 DOI: 10.1186/s12951-023-01770-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 01/05/2023] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic nonspecific disease with unknown etiology. Currently, the anti-inflammatory therapeutic approaches have achieved a certain extent of effects in terms of inflammation alleviation. Still, the final pathological outcome of intestinal fibrosis has not been effectively improved yet. RESULTS In this study, dextran-coated cerium oxide (D-CeO2) nanozyme with superoxide dismutase (SOD) and catalase (CAT) activities was synthesized by chemical precipitation. Our results showed that D-CeO2 could efficiently scavenge reactive oxide species (ROS) as well as downregulate the pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and iNOS) to protect cells from H2O2-induced oxidative damage. Moreover, D-CeO2 could suppress the expression of fibrosis-related gene levels, such as α-SMA, and Collagen 1/3, demonstrating the anti-fibrotic effect. In both TBNS- and DSS-induced colitis models, oral administration of D-CeO2 in chitosan/alginate hydrogel alleviated intestinal inflammation, reduced colonic damage by scavenging ROS, and decreased inflammatory factor levels. Notably, our findings also suggested that D-CeO2 reduced fibrosis-related cytokine levels, predicting a contribution to alleviating colonic fibrosis. Meanwhile, D-CeO2 could also be employed as a CT contrast agent for noninvasive gastrointestinal tract (GIT) imaging. CONCLUSION We introduced cerium oxide nanozyme as a novel therapeutic approach with computed tomography (CT)-guided anti-inflammatory and anti-fibrotic therapy for the management of IBD. Collectively, without appreciable systemic toxicity, D-CeO2 held the promise of integrated applications for diagnosis and therapy, pioneering the exploration of nanozymes with ROS scavenging capacity in the anti-fibrotic treatment of IBD.
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Affiliation(s)
- Yameng Cao
- grid.452438.c0000 0004 1760 8119Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243School of Basic Medical Sciences, Xian Key Laboratory of Immune Related Diseases, Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243Key Laboratory of Environment and Genes Related to Diseases, Xian Jiaotong University, Ministry of Education, Xi’an, 710061 Shaanxi China
| | - Kai Cheng
- grid.33199.310000 0004 0368 7223Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics - Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074 Hubei China
| | - Mei Yang
- grid.452438.c0000 0004 1760 8119Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243School of Basic Medical Sciences, Xian Key Laboratory of Immune Related Diseases, Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243Key Laboratory of Environment and Genes Related to Diseases, Xian Jiaotong University, Ministry of Education, Xi’an, 710061 Shaanxi China
| | - Zhichao Deng
- grid.452438.c0000 0004 1760 8119Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243School of Basic Medical Sciences, Xian Key Laboratory of Immune Related Diseases, Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243Key Laboratory of Environment and Genes Related to Diseases, Xian Jiaotong University, Ministry of Education, Xi’an, 710061 Shaanxi China
| | - Yana Ma
- grid.452438.c0000 0004 1760 8119Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243School of Basic Medical Sciences, Xian Key Laboratory of Immune Related Diseases, Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243Key Laboratory of Environment and Genes Related to Diseases, Xian Jiaotong University, Ministry of Education, Xi’an, 710061 Shaanxi China
| | - Xiangji Yan
- grid.452438.c0000 0004 1760 8119Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243School of Basic Medical Sciences, Xian Key Laboratory of Immune Related Diseases, Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243Key Laboratory of Environment and Genes Related to Diseases, Xian Jiaotong University, Ministry of Education, Xi’an, 710061 Shaanxi China
| | - Yuanyuan Zhang
- grid.452438.c0000 0004 1760 8119Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243School of Basic Medical Sciences, Xian Key Laboratory of Immune Related Diseases, Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243Key Laboratory of Environment and Genes Related to Diseases, Xian Jiaotong University, Ministry of Education, Xi’an, 710061 Shaanxi China
| | - Zhenzhen Jia
- grid.452438.c0000 0004 1760 8119Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243School of Basic Medical Sciences, Xian Key Laboratory of Immune Related Diseases, Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243Key Laboratory of Environment and Genes Related to Diseases, Xian Jiaotong University, Ministry of Education, Xi’an, 710061 Shaanxi China
| | - Jun Wang
- grid.452438.c0000 0004 1760 8119Department of Emergency and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061 China
| | - Kangsheng Tu
- grid.452438.c0000 0004 1760 8119Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xian Jiaotong University, Xi’an, 710061 Shaanxi China
| | - Jie Liang
- grid.417295.c0000 0004 1799 374XXijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an, 710068 Shaanxi China
| | - Mingzhen Zhang
- grid.452438.c0000 0004 1760 8119Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243School of Basic Medical Sciences, Xian Key Laboratory of Immune Related Diseases, Xian Jiaotong University, Xi’an, 710061 Shaanxi China ,grid.43169.390000 0001 0599 1243Key Laboratory of Environment and Genes Related to Diseases, Xian Jiaotong University, Ministry of Education, Xi’an, 710061 Shaanxi China
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12
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Vieujean S, Loly JP, Boutaffala L, Meunier P, Reenaers C, Briquet A, Lechanteur C, Baudoux E, Beguin Y, Louis E. Mesenchymal Stem Cell Injection in Crohn's Disease Strictures: A Phase I-II Clinical Study. J Crohns Colitis 2022; 16:506-510. [PMID: 34473270 DOI: 10.1093/ecco-jcc/jjab154] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND AIM Mesenchymal stem cells [MSCs] have anti-inflammatory and anti-fibrotic properties and could be a potential therapy for Crohn's disease [CD] strictures. In this phase I-II pilot trial, we assessed safety and efficacy of local MSC injection to treat CD strictures. METHODS CD patients with a short [less than 5 cm in length] non-passable stricture accessible by ileocolonoscopy were included. Allogenic bone-marrow derived MSCs were injected in the four quadrants of the stricture. Adverse events and clinical scores were evaluated at each follow-up visit and endoscopy and magnetic resonance enterography were performed at baseline, Week [W]12 and W48. The main judgement criterion for efficacy was the complete [defined by the ability to pass the ileocolonoscope] or partial [defined by a diameter increase] resolution of the stricture at W12. Second efficacy criteria included assessment of the stricture at W48 and evolution of clinical scores at W12 and W48. RESULTS We performed 11 MSC injections in 10 CD patients [three primary and seven anastomotic strictures; one stricture injected twice]. MSC injections were well tolerated but four hospitalisations for occlusion were reported. At W12, five patients presented a complete or partial resolution of the stricture [two complete and three partial]. Seven patients were re-evaluated at W48 [one dilated, one operated, and one lost to follow-up] and four patients had a complete resolution. The evolution of clinical scores between W0, W12, and W48 was not statistically significant. CONCLUSIONS MSCs injection in CD stricture was well tolerated and may offer a benefit.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | - Jean-Philippe Loly
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | - Layla Boutaffala
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | - Paul Meunier
- Department of Radiology, University Hospital CHU of Liège, Liège, Belgium
| | - Catherine Reenaers
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | - Alexandra Briquet
- Laboratory of Cell and Gene Therapy [LTCG], University Hospital CHU of Liège, Liège, Belgium
| | - Chantal Lechanteur
- Laboratory of Cell and Gene Therapy [LTCG], University Hospital CHU of Liège, Liège, Belgium
| | - Etienne Baudoux
- Laboratory of Cell and Gene Therapy [LTCG], University Hospital CHU of Liège, Liège, Belgium
| | - Yves Beguin
- Laboratory of Cell and Gene Therapy [LTCG], University Hospital CHU of Liège, Liège, Belgium.,Department of Hematology, University Hospital CHU of Liège and University of Liège, Liège, Belgium
| | - Edouard Louis
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
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13
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Ta AD, Ollberding NJ, Karns R, Haberman Y, Alazraki AL, Hercules D, Baldassano R, Markowitz J, Heyman MB, Kim S, Kirschner B, Shapiro JM, Noe J, Oliva-Hemker M, Otley A, Pfefferkorn M, Kellermayer R, Snapper S, Rabizadeh S, Xavier R, Dubinsky M, Hyams J, Kugathasan S, Jegga AG, Dillman JR, Denson LA. Association of Baseline Luminal Narrowing With Ileal Microbial Shifts and Gene Expression Programs and Subsequent Transmural Healing in Pediatric Crohn Disease. Inflamm Bowel Dis 2021; 27:1707-1718. [PMID: 33452801 PMCID: PMC8528150 DOI: 10.1093/ibd/izaa339] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Indexed: 12/29/2022]
Abstract
BACKGROUND Transmural healing (TH) is associated with better long-term outcomes in Crohn disease (CD), whereas pretreatment ileal gene signatures encoding myeloid inflammatory responses and extracellular matrix production are associated with stricturing. We aimed to develop a predictive model for ileal TH and to identify ileal genes and microbes associated with baseline luminal narrowing (LN), a precursor to strictures. MATERIALS AND METHODS Baseline small bowel imaging obtained in the RISK pediatric CD cohort study was graded for LN. Ileal gene expression was determined by RNASeq, and the ileal microbial community composition was characterized using 16S rRNA amplicon sequencing. Clinical, demographic, radiologic, and genomic variables were tested for association with baseline LN and future TH. RESULTS After controlling for ileal location, baseline ileal LN (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-0.8), increasing serum albumin (OR, 4; 95% CI, 1.3-12.3), and anti-Saccharomyces cerevisiae antibodies IgG serology (OR, 0.97; 95% CI, 0.95-1) were associated with subsequent TH. A multivariable regression model including these factors had excellent discriminant power for TH (area under the curve, 0.86; positive predictive value, 80%; negative predictive value, 87%). Patients with baseline LN exhibited increased Enterobacteriaceae and inflammatory and extracellular matrix gene signatures, coupled with reduced levels of butyrate-producing commensals and a respiratory electron transport gene signature. Taxa including Lachnospiraceae and the genus Roseburia were associated with increased respiratory and decreased inflammatory gene signatures, and Aggregatibacter and Blautia bacteria were associated with reduced extracellular matrix gene expression. CONCLUSIONS Pediatric patients with CD with LN at diagnosis are less likely to achieve TH. The association between specific microbiota, wound healing gene programs, and LN may suggest future therapeutic targets.
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Affiliation(s)
- Allison D Ta
- Cincinnati Children’s Medical Hospital Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Nicholas J Ollberding
- Cincinnati Children’s Medical Hospital Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Rebekah Karns
- Cincinnati Children’s Medical Hospital Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Yael Haberman
- Cincinnati Children’s Medical Hospital Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Sheba Medical Center, Tel-HaShomer, affiliated with the Tel-Aviv University, Tel Aviv, Israel
| | - Adina L Alazraki
- Emory University and Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - David Hercules
- Emory University and Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Robert Baldassano
- The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - James Markowitz
- Cohen Children’s Medical Center of New York, New Hyde Park, New York, USA
| | - Melvin B Heyman
- University of California San Francisco, San Francisco, California, USA
| | - Sandra Kim
- Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA
| | | | | | - Joshua Noe
- Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | | | | | | | - Richard Kellermayer
- Texas Children’s Hospital, Baylor College School of Medicine, Houston, Texas, USA
| | - Scott Snapper
- Children’s Hospital-Boston, Boston, Massachusetts, USA
| | | | - Ramnik Xavier
- Broad Institute at Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- Massachusetts General Hospital, Cambridge, Massachusetts, USA
| | | | - Jeffrey Hyams
- Connecticut Children’s Medical Center, Hartford, Connecticut, USA
| | - Subra Kugathasan
- Emory University and Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Anil G Jegga
- Cincinnati Children’s Medical Hospital Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Jonathan R Dillman
- Cincinnati Children’s Medical Hospital Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Lee A Denson
- Cincinnati Children’s Medical Hospital Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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14
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Ou W, Xu W, Liu F, Guo Y, Huang Z, Feng T, Liu CY, Du P. Increased expression of yes-associated protein/YAP and transcriptional coactivator with PDZ-binding motif/TAZ activates intestinal fibroblasts to promote intestinal obstruction in Crohn's disease. EBioMedicine 2021; 69:103452. [PMID: 34186485 PMCID: PMC8243379 DOI: 10.1016/j.ebiom.2021.103452] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 05/29/2021] [Accepted: 06/02/2021] [Indexed: 12/18/2022] Open
Abstract
Background Intestinal obstruction caused by intestinal fibrosis is a common and serious complication of Crohn's disease (CD). Intestinal fibroblasts, the main effector cells mediating gastrointestinal fibrosis, are activated during chronic inflammation. However, the mechanism of fibroblast activation in CD has not been well elucidated. Methods Fibroblasts isolated from stenotic and nonstenotic intestines of CD patients were used for RNA sequencing. Immunohistochemical and immunofluorescent staining was performed to evaluate the correlation between intestinal fibrosis and YAP/TAZ expression in our CD cohort and a DSS-induced chronic colitis murine model. A Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) inhibitor was used to explore the ROCK1-YAP/TAZ axis in intestinal fibroblasts in vitro and DSS-induced chronic colitis murine model in vivo. Findings The expression of YAP/TAZ was significantly upregulated in stenotic fibroblasts, which was associated with the YAP/TAZ target gene signature. YAP/TAZ knockdown suppressed the activation of intestinal fibroblasts. In intestinal fibroblasts, YAP/TAZ were activated by the Rho-ROCK1 signalling pathway. High YAP/TAZ expression was positively correlated with ROCK1 expression, which is a prognostic marker for intestinal obstruction in CD patients. Interpretation YAP/TAZ activation can lead to fibroblast activation and intestinal obstruction in CD. The effect of ROCK1 inhibitor on alleviating intestinal fibrosis is associated with YAP/TAZ inhibition. Targeted inhibition of YAP/TAZ in fibroblasts may be a potential therapeutic strategy to suppress intestinal fibrosis in CD. Funding This work was supported by the National Key R&D Program of China (2019YFC1316002), the NSFC (81873547, 82073201, 81874177, 82000481) and the Shanghai Sailing Program (20YF1429400).
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Affiliation(s)
- Weijun Ou
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Weimin Xu
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Fangyuan Liu
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Yuegui Guo
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Zhenyu Huang
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Tienan Feng
- Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Chen-Ying Liu
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
| | - Peng Du
- Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
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15
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A novel identification system combining diffusion kurtosis imaging with conventional magnetic resonance imaging to assess intestinal strictures in patients with Crohn's disease. Abdom Radiol (NY) 2021; 46:936-947. [PMID: 32964274 DOI: 10.1007/s00261-020-02765-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 09/04/2020] [Accepted: 09/10/2020] [Indexed: 01/16/2023]
Abstract
PURPOSE To determine the utility of diffusion kurtosis imaging (DKI) for assessing bowel fibrosis and to establish a new magnetic resonance imaging (MRI)-based classification based on DKI and conventional MRI parameters for characterizing intestinal strictures in Crohn's disease (CD) using the histological evaluation of resected intestine samples as the reference standard. METHODS Thirty-one patients with CD undergoing preoperative conventional MRI and diffusion-weighted imaging (DWI) (b values = 0-2000 s/mm2) were consecutively enrolled. We classified the mural T2-weighted signal intensity and arterial-phase enhancement patterns on conventional MRI. We also measured DWI-derived apparent diffusion coefficients (ADCs) and DKI-derived apparent diffusion for non-Gaussian distribution (Dapp) and apparent diffusional kurtosis (Kapp). A new MRI-based classification was established to characterize intestinal strictures in CD. Its performance was validated in nine additional patients with CD. RESULTS Histological inflammation grades were significantly correlated to T2-weighted signal intensity (r = 0.477; P < 0.001) and ADC (r = - 0.226; P = 0.044). Histological fibrosis grades were moderately correlated to Kapp (r = 0.604, P < 0.001); they were also correlated to Dapp (r = - 0.491; P < 0.001) and ADC (r = - 0.270; P = 0.015). T2-weighted signal intensity could differentiate between no-to-mild and moderate-to-severe bowel inflammation (sensitivity, 0.970; specificity, 0.479). Kapp could differentiate between no-to-mild and moderate-to-severe bowel fibrosis (sensitivity, 0.959; specificity, 0.781). The agreement between the new MRI-based classification and the histological classification was moderate in the test (κ = 0.507; P < 0.001) and validation (κ = 0.530; P < 0.001) sets. CONCLUSIONS DKI can be used to assess bowel fibrosis. The new MRI-based classification can help to distinguish between fibrotic and inflammatory intestinal strictures in patients with CD.
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16
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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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17
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Cui Y, Zhang M, Leng C, Blokzijl T, Jansen BH, Dijkstra G, Faber KN. Pirfenidone Inhibits Cell Proliferation and Collagen I Production of Primary Human Intestinal Fibroblasts. Cells 2020; 9:cells9030775. [PMID: 32235767 PMCID: PMC7140656 DOI: 10.3390/cells9030775] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 03/16/2020] [Accepted: 03/20/2020] [Indexed: 12/12/2022] Open
Abstract
Intestinal fibrosis is a common complication of inflammatory bowel disease. So far, there is no safe and effective drug for intestinal fibrosis. Pirfenidone is an anti-fibrotic compound available for the treatment of idiopathic pulmonary fibrosis. Here, we explored the anti-proliferative and anti-fibrotic properties of pirfenidone on primary human intestinal fibroblasts (p-hIFs). p-hIFs were cultured in the absence and presence of pirfenidone. Cell proliferation was measured by a real-time cell analyzer (xCELLigence) and BrdU incorporation. Cell motility was monitored by live cell imaging. Cytotoxicity and cell viability were analyzed by Sytox green, Caspase-3 and Water Soluble Tetrazolium Salt-1 (WST-1) assays. Gene expression of fibrosis markers was determined by quantitative reverse transcription PCR (RT-qPCR). The mammalian target of rapamycin (mTOR) signaling was analyzed by Western blotting and type I collagen protein expression additionally by immunofluorescence microscopy. Pirfenidone dose-dependently inhibited p-hIF proliferation and motility, without inducing cell death. Pirfenidone suppressed mRNA levels of genes that contribute to extracellular matrix production, as well as basal and TGF-β1-induced collagen I protein production, which was associated with inhibition of the rapamycin-sensitive mTOR/p70S6K pathway in p-hIFs. Thus, pirfenidone inhibits the proliferation of intestinal fibroblasts and suppresses collagen I production through the TGF-β1/mTOR/p70S6K signaling pathway, which might be a novel and safe anti-fibrotic strategy to treat intestinal fibrosis.
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Affiliation(s)
- Yingying Cui
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (Y.C.); (M.Z.); (T.B.); (B.H.J.); (G.D.)
| | - Mengfan Zhang
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (Y.C.); (M.Z.); (T.B.); (B.H.J.); (G.D.)
| | - Changsen Leng
- Department of Biomedical Sciences of Cells and Systems, section Molecular Cell Biology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
| | - Tjasso Blokzijl
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (Y.C.); (M.Z.); (T.B.); (B.H.J.); (G.D.)
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
| | - Bernadien H. Jansen
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (Y.C.); (M.Z.); (T.B.); (B.H.J.); (G.D.)
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (Y.C.); (M.Z.); (T.B.); (B.H.J.); (G.D.)
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (Y.C.); (M.Z.); (T.B.); (B.H.J.); (G.D.)
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands
- Correspondence: ; Tel.: +31-50-3612364
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18
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Meng J, Huang S, Sun C, Zhang ZW, Mao R, Yang YH, Feng ST, Li ZP, Li X. Comparison of Three Magnetization Transfer Ratio Parameters for Assessment of Intestinal Fibrosis in Patients with Crohn's Disease. Korean J Radiol 2020; 21:290-297. [PMID: 32090521 PMCID: PMC7039729 DOI: 10.3348/kjr.2019.0217] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 11/07/2019] [Indexed: 01/13/2023] Open
Abstract
OBJECTIVE To establish a novel standardized magnetization transfer ratio (MTR) parameter which considers the element of the normal bowel wall and to compare the efficacy of the MTR, normalized MTR, and standardized MTR in evaluating intestinal fibrosis in Crohn's disease (CD). MATERIALS AND METHODS Abdominal magnetization transfer imaging from 20 consecutive CD patients were analyzed before performing elective operations. MTR parameters were calculated by delineating regions of interest in specified segments on MTR maps. Specimens with pathologically confirmed bowel fibrosis were classified into one of four severity grades. The correlation between MTR parameters and fibrosis score was tested by Spearman's rank correlation. Differences in MTR, normalized MTR, and standardized MTR across diverse histologic fibrosis scores were analyzed using the independent sample t test or the Mann-Whitney U test. The area under the receiver operating characteristic curve (AUC) was computed to test the efficacies of the MTR parameters in differentiating severe intestinal fibrosis from mild-to-moderate fibrosis. RESULTS Normalized (r = 0.700; p < 0.001) and standardized MTR (r = 0.695; p < 0.001) showed a strong correlation with bowel fibrosis scores, followed by MTR (r = 0.590; p < 0.001). Significant differences in MTR (t = -4.470; p < 0.001), normalized MTR (Z = -5.003; p < 0.001), and standardized MTR (Z = -5.133; p < 0.001) were found between mild-to-moderate and severe bowel fibrosis. Standardized MTR (AUC = 0.895; p < 0.001) had the highest accuracy in differentiating severe bowel fibrosis from mild-to-moderate bowel wall fibrosis, followed by normalized MTR (AUC = 0.885; p < 0.001) and MTR (AUC = 0.798; p < 0.001). CONCLUSION Standardized MTR is slightly superior to MTR and normalized MTR and therefore may be an optimal parameter for evaluating the severity of intestinal fibrosis in CD.
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Affiliation(s)
- Jixin Meng
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Siyun Huang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - CanHui Sun
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhong Wei Zhang
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yan Hong Yang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shi Ting Feng
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zi Ping Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - XueHua Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
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19
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Torle J, Dabir PD, Korsgaard U, Christiansen J, Qvist N, El-Hussuna A. Levels of Intestinal Inflammation and Fibrosis in Resection Specimens after Preoperative Anti-Tumor Necrosis Factor Alpha Treatment in Patients with Crohn's Disease: A Comparative Pilot Study. Surg Res Pract 2020; 2020:6085678. [PMID: 32149183 PMCID: PMC7054778 DOI: 10.1155/2020/6085678] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 01/13/2020] [Accepted: 02/04/2020] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Strictures are a common complication in Crohn's disease (CD), found in more than 50% of patients. They are characterized by the excessive deposition of extracellular proteins in the tissue as a result of the chronic inflammatory process. The effect of anti-tumor necrosis factor alpha (TNF-α) therapy on the development of fibrosis is not yet fully understood. AIM To investigate whether the degree of intestinal inflammation and fibrosis is correlated with preoperative anti-TNF-α) therapy on the development of fibrosis is not yet fully understood. METHODS This unblinded, prospective, single tertiary center, pilot cohort study included all adult patients with CD who underwent elective, laparoscopic, or open intestinal resection. Preoperative investigations included measurement of blood TNF-α) therapy on the development of fibrosis is not yet fully understood. RESULTS Histopathological specimens from 10 patients with CD who underwent ileocecal or ileocolic resections were retrieved. Four of those patients were on anti-TNF-α) therapy on the development of fibrosis is not yet fully understood. α) therapy on the development of fibrosis is not yet fully understood. α) therapy on the development of fibrosis is not yet fully understood. p=0.01). Anti-TNF-α) therapy on the development of fibrosis is not yet fully understood. α) therapy on the development of fibrosis is not yet fully understood. α) therapy on the development of fibrosis is not yet fully understood. CONCLUSIONS Patients who underwent preoperative anti-TNF-α treatment had a higher fibrosis score than controls.α) therapy on the development of fibrosis is not yet fully understood.
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Affiliation(s)
- J. Torle
- Department of Surgery, Regional Hospital Randers, Midt-Jylland region, Randers, Denmark
| | - P. D. Dabir
- Department of Pathology, Regional Hospital Randers, Midt-Jylland region, Randers, Denmark
| | - U. Korsgaard
- Department of Pathology, Regional Hospital Randers, Midt-Jylland region, Randers, Denmark
| | - J. Christiansen
- Department of Pathology, Regional Hospital Randers, Midt-Jylland region, Randers, Denmark
| | - N. Qvist
- IBD Care, Surgical Research Unit, Odense University Hospital, Southern University of Denmark, region Syd Danmark, Randers, Denmark
| | - A. El-Hussuna
- Department of Surgery, Aalborg University Hospital, Aalborg, Nord-Jylland region, Denmark
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20
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A novel collagen area fraction index to quantitatively assess bowel fibrosis in patients with Crohn's disease. BMC Gastroenterol 2019; 19:180. [PMID: 31711420 PMCID: PMC6849306 DOI: 10.1186/s12876-019-1100-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 10/29/2019] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND A validated histopathological tool to precisely evaluate bowel fibrosis in patients with Crohn's disease is lacking. We attempted to establish a new index to quantify the severity of bowel fibrosis in patients with Crohn's disease-associated fibrostenosis. METHODS We analyzed the histopathological data of 31 patients with Crohn's disease strictures undergoing surgical resection. The most representative sections of resected strictured segments were stained with Masson trichrome to manifest bowel fibrosis. The collagen area fraction and histological fibrosis score were simultaneously calculated for the same section to evaluate the severity of bowel fibrosis. RESULTS Collagen area fraction strongly correlated with histological fibrosis scores (r = 0.733, P < 0.001). It showed a stronger correlation (r = 0.561, P < 0.001) with the degree of bowel strictures than the histological fibrosis score did (r = 0.468, P < 0.001). It was also shown to be more accurate for diagnosing Crohn's disease strictures (area under the receiver operating characteristic curve = 0.815, P < 0.001) compared with the histological fibrosis score (area under the curve = 0.771, P < 0.001). High repeatability was observed for the collagen area fraction, with an intraclass correlation coefficient of 0.915 (P < 0.001). CONCLUSIONS Collagen area fraction is a simple and reliable index to quantify the severity of bowel fibrosis in patients with Crohn's disease-associated fibrostenosis.
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21
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Grass F, Fletcher JG, Alsughayer A, Petersen M, Bruining DH, Bartlett DJ, Mathis KL, Lightner AL. Development of an Objective Model to Define Near-Term Risk of Ileocecal Resection in Patients with Terminal Ileal Crohn Disease. Inflamm Bowel Dis 2019; 25:1845-1853. [PMID: 31050733 DOI: 10.1093/ibd/izz079] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND The decision to either escalate medical therapy or proceed to ileocecal resection (ICR) in patients with terminal ileal Crohn disease (CD) remains largely subjective. We sought to develop a risk score for predicting ICR at 1 year from computed tomography or magnetic resonance enterography (CTE/MRE). METHODS We conducted a retrospective cohort study including all consecutive adult (> 18 years) patients with imaging findings of terminal ileal CD (Montreal classification: B1, inflammatory predominant; B2, stricturing; or B3, penetrating) on CTE/MRE between January 1, 2016, and December 31, 2016. The risk for ICR at 6 months and at 1 year of CTE/MRE and risk factors associated with ICR, including demographics, CD-specific immunosuppressive therapeutics, and disease presentation at the time of imaging, were determined. RESULTS Of 559 patients, 121 (21.6%) underwent ICR during follow-up (1.4 years [IQR 0.21-1.64 years]); the risk for ICR at 6 months and at 1 year was 18.2% (95% CI 14.7%-21.6%) and 20.5% (95% CI 16.8%-24.1%), respectively. Multivariable analysis revealed Montreal classification (B2, hazard ratio [HR] 2.73, and B3, HR 6.80, both P < 0.0001), upstream bowel dilation (HR 3.06, P < 0.0001), and younger age (19-29 years reference, 30-44 years, HR 0.83 [P = 0.40]; 45-59 years, HR 0.58 [P = 0.04], and 60+ years, HR 0.45 [P = 0.01]) to significantly increase the likelihood of ICR. A predictive nomogram for interval ICR was developed based on these significant variables. CONCLUSIONS The presence of CD strictures, penetrating complications, and upstream bowel dilation on CTE/MRE, combined with young age, significantly predict ICR. The suggested risk model may facilitate objective therapeutic decision-making.
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Affiliation(s)
- Fabian Grass
- Department of Colon and Rectal Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Joel G Fletcher
- Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ahmad Alsughayer
- Department of Colon and Rectal Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Molly Petersen
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - David H Bruining
- Department of Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Kellie L Mathis
- Department of Colon and Rectal Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Amy L Lightner
- Department of Colon and Rectal Surgery, Mayo Clinic, Rochester, Minnesota, USA
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22
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Mortensen JH, Lindholm M, Langholm LL, Kjeldsen J, Bay-Jensen AC, Karsdal MA, Manon-Jensen T. The intestinal tissue homeostasis - the role of extracellular matrix remodeling in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2019; 13:977-993. [PMID: 31587588 DOI: 10.1080/17474124.2019.1673729] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Introduction: Extracellular matrix (ECM) remodeling of the intestinal tissue is important in inflammatory bowel disease (IBD) due to the extensive mucosal remodeling. There are still gaps in our knowledge as to how ECM remodeling is related to intestinal epithelium homeostasis and healing of the intestinal mucosa.Areas covered: The aim of this review is to highlight the importance of the ECM in relation to the pathogenesis of IBD, while addressing basement membrane and interstitial matrix remodeling, and the processes of wound healing of the intestinal tissue in IBD.Expert opinion: In IBD, basement membrane remodeling may reflect the integrity of the intestinal epithelial-cell homeostasis. The interstitial matrix remodeling is associated with deep inflammation such as the transmural inflammation as seen in fistulas and intestinal fibrosis leading to fibrostenotic strictures, in patients with CD. The interplay between wound healing processes and ECM remodeling also affects the tissue homeostasis in IBD. The interstitial matrix, produced by fibroblasts, holds a very different biology as compared to the epithelial basement membrane in IBD. In combination with integration of wound healing, quantifying the interplay between damage and repair to these sub compartments may provide essential information in IBD patient profiling, mucosal healing and disease management.
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Affiliation(s)
- J H Mortensen
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - M Lindholm
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark.,Department of Medical Gastroenterology, Odense University hospital, Odense, Denmark
| | - L L Langholm
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - J Kjeldsen
- Department of Medical Gastroenterology, Odense University hospital, Odense, Denmark
| | - A C Bay-Jensen
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - M A Karsdal
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - T Manon-Jensen
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
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23
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Kirov S, Sasson A, Zhang C, Chasalow S, Dongre A, Steen H, Stensballe A, Andersen V, Birkelund S, Bennike TB. Degradation of the extracellular matrix is part of the pathology of ulcerative colitis. Mol Omics 2019; 15:67-76. [PMID: 30702115 DOI: 10.1039/c8mo00239h] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The scientific value of re-analyzing existing datasets is often proportional to the complexity of the data. Proteomics data are inherently complex and can be analyzed at many levels, including proteins, peptides, and post-translational modifications to verify and/or develop new hypotheses. In this paper, we present our re-analysis of a previously published study comparing colon biopsy samples from ulcerative colitis (UC) patients to non-affected controls. We used a different statistical approach, employing a linear mixed-effects regression model and analyzed the data both on the protein and peptide level. In addition to confirming and reinforcing the original finding of upregulation of neutrophil extracellular traps (NETs), we report novel findings, including that Extracellular Matrix (ECM) degradation and neutrophil maturation are involved in the pathology of UC. The pharmaceutically most relevant differential protein expressions were confirmed using immunohistochemistry as an orthogonal method. As part of this study, we also compared proteomics data to previously published mRNA expression data. These comparisons indicated compensatory regulation at transcription levels of the ECM proteins we identified and open possible new avenues for drug discovery.
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Affiliation(s)
- Stefan Kirov
- Translational Bioinformatics, Bristol Myers Squib, Pennington, NJ, USA.
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Argollo M, Gilardi D, Roda G, Fiorino G, Peyrin-Biroulet L, Danese S. Anti-fibrotic Drugs for Crohn’s Disease: Ready for Prime Time? Curr Pharm Des 2019; 25:47-56. [DOI: 10.2174/1381612825666190308100844] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Accepted: 03/01/2019] [Indexed: 12/17/2022]
Abstract
Intestinal fibrosis, driven by chronic inflammation in Crohn’s disease, can be defined as an excessive
accumulation of extracellular matrix in the affected gut segment ultimately leading to an impaired wound healing
and cumulative tissue damage, possibly resulting in organ dysfunction, formation of stenotic lesions and necessity
of surgical intervention. Despite continuous advances in developing novel treatment modalities targeting different
pathways to control chronic gut inflammation in CD, no effective anti-fibrotic agents have been released, to date.
Thus, a better understanding of the molecular and cellular mechanisms underlying intestinal fibrosis is key to
move this area of investigation forward.
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Affiliation(s)
- Marjorie Argollo
- IBD Centre, Humanitas Clinical and Research Centre, Rozzano, Milan, Italy
| | - Daniela Gilardi
- IBD Centre, Humanitas Clinical and Research Centre, Rozzano, Milan, Italy
| | - Giulia Roda
- IBD Centre, Humanitas Clinical and Research Centre, Rozzano, Milan, Italy
| | - Gionata Fiorino
- IBD Centre, Humanitas Clinical and Research Centre, Rozzano, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre, France
| | - Silvio Danese
- IBD Centre, Humanitas Clinical and Research Centre, Rozzano, Milan, Italy
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25
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Lovisa S, Genovese G, Danese S. Role of Epithelial-to-Mesenchymal Transition in Inflammatory Bowel Disease. J Crohns Colitis 2019; 13:659-668. [PMID: 30520951 DOI: 10.1093/ecco-jcc/jjy201] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Intestinal fibrosis is an inevitable complication in patients with inflammatory bowel disease [IBD], occurring in its two major clinical manifestations: ulcerative colitis and Crohn's disease. Fibrosis represents the final outcome of the host reaction to persistent inflammation, which triggers a prolonged wound healing response resulting in the excessive deposition of extracellular matrix, eventually leading to intestinal dysfunction. The process of epithelial-to-mesenchymal transition [EMT] represents an embryonic program relaunched during wound healing, fibrosis and cancer. Here we discuss the initial observations and the most recent findings highlighting the role of EMT in IBD-associated intestinal fibrosis and fistulae formation. In addition, we briefly review knowledge on the cognate process of endothelial-to-mesenchymal transition [EndMT]. Understanding EMT functionality and the molecular mechanisms underlying the activation of this mesenchymal programme will permit designing new therapeutic strategies to halt the fibrogenic response in the intestine.
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Affiliation(s)
- Sara Lovisa
- Department of Cancer Biology, Metastasis Research Center, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Giannicola Genovese
- Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.,Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Silvio Danese
- IBD Center, Department of Gastroenterology, Humanitas Research Hospital, Rozzano, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy
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26
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Li Yim AYF, de Bruyn JR, Duijvis NW, Sharp C, Ferrero E, de Jonge WJ, Wildenberg ME, Mannens MMAM, Buskens CJ, D’Haens GR, Henneman P, te Velde AA. A distinct epigenetic profile distinguishes stenotic from non-inflamed fibroblasts in the ileal mucosa of Crohn's disease patients. PLoS One 2018; 13:e0209656. [PMID: 30589872 PMCID: PMC6307755 DOI: 10.1371/journal.pone.0209656] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 12/10/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The chronic remitting and relapsing intestinal inflammation characteristic of Crohn's disease frequently leads to fibrosis and subsequent stenosis of the inflamed region. Approximately a third of all Crohn's disease patients require resection at some stage in their disease course. As the pathogenesis of Crohn's disease associated fibrosis is largely unknown, a strong necessity exists to better understand the pathophysiology thereof. METHODS In this study, we investigated changes of the DNA methylome and transcriptome of ileum-derived fibroblasts associated to the occurrence of Crohn's disease associated fibrosis. Eighteen samples were included in a DNA methylation array and twenty-one samples were used for RNA sequencing. RESULTS Most differentially methylated regions and differentially expressed genes were observed when comparing stenotic with non-inflamed samples. By contrast, few differences were observed when comparing Crohn's disease with non-Crohn's disease, or inflamed with non-inflamed tissue. Integrative methylation and gene expression analyses revealed dysregulation of genes associated to the PRKACA and E2F1 network, which is involved in cell cycle progression, angiogenesis, epithelial to mesenchymal transition, and bile metabolism. CONCLUSION Our research provides evidence that the methylome and the transcriptome are systematically dysregulated in stenosis-associated fibroblasts.
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Affiliation(s)
- Andrew Y. F. Li Yim
- Genome Diagnostics Laboratory, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom
| | - Jessica R. de Bruyn
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Department of Gastroenterology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Nicolette W. Duijvis
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Catriona Sharp
- Epigenetics Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom
| | - Enrico Ferrero
- Computational Biology, Target Sciences, GlaxoSmithKline, Stevenage, United Kingdom
| | - Wouter J. de Jonge
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Manon E. Wildenberg
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Marcel M. A. M. Mannens
- Genome Diagnostics Laboratory, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Christianne J. Buskens
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Geert R. D’Haens
- Department of Gastroenterology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Peter Henneman
- Genome Diagnostics Laboratory, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Anje A. te Velde
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- * E-mail:
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IVIM with fractional perfusion as a novel biomarker for detecting and grading intestinal fibrosis in Crohn’s disease. Eur Radiol 2018; 29:3069-3078. [DOI: 10.1007/s00330-018-5848-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 10/03/2018] [Accepted: 10/22/2018] [Indexed: 01/18/2023]
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Zhang HJ, Zhang YN, Zhou H, Guan L, Li Y, Sun MJ. IL-17A Promotes Initiation and Development of Intestinal Fibrosis Through EMT. Dig Dis Sci 2018; 63:2898-2909. [PMID: 30097894 DOI: 10.1007/s10620-018-5234-x] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 07/31/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Intestinal fibrosis is a common complication of Crohn's disease (CD). Its exact mechanism is still unclear, and effective treatments to control or reverse the fibrosis process are unavailable. Epithelial-mesenchymal transition (EMT) may promote intestinal fibrosis by increasing deposition of extracellular matrix protein. IL-17A is a pro-inflammatory cytokine, and it has been shown as a profibrotic factor as its association with fibrosis of multiple organs was reported. AIMS To assess the roles of IL-17A and EMT in the initiation and development of intestinal fibrosis and to verify the potential inductive effect of IL-17A on EMT. METHODS In this study, we evaluated the expression of IL-17A and EMT-related genes in colonic mucosal biopsy tissues of CD patients and control individuals. Then, we examined the changes of EMT-related genes and fibrosis-related genes of IEC-6 cells which cultured for 72 h under increasing concentrations of IL-17A or with TGF-β1, to verify the potential inductive effect of IL-17A on EMT in vitro. We blocked the IL-17A of the mouse model of TNBS-induced experimental intestinal colitis and fibrosis to further verify the potential inductive effect of IL-17A on EMT in vivo. RESULTS We found the occurrence of EMT and high-level expression of IL-17A in intestinal mucosa of CD patients. Using IEC-6 cells, we showed that IL-17A may induce EMT in intestinal epithelial cells that come with reduced E-cadherin expression and increased expression of vimentin, snail, and α-SMA. We further found that anti-IL-17A treatment alleviated intestinal fibrosis through reducing EMT in mouse intestine. CONCLUSIONS Our study confirmed the involvement of IL-17A in the development of intestinal fibrosis through inducing EMT.
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Affiliation(s)
- Hui-Jing Zhang
- Department of Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yi-Ning Zhang
- Department of Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Huan Zhou
- Department of Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Lin Guan
- Department of Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yue Li
- Department of Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ming-Jun Sun
- Department of Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
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29
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de Bruyn M, Ferrante M. Failure of MMP-9 Antagonists in IBD: Demonstrating the Importance of Molecular Biology and Well-Controlled Early Phase Studies. J Crohns Colitis 2018; 12:1011-1013. [PMID: 30010739 DOI: 10.1093/ecco-jcc/jjy102] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 06/29/2018] [Accepted: 07/12/2018] [Indexed: 12/23/2022]
Affiliation(s)
- Magali de Bruyn
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Marc Ferrante
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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30
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Sferra R, Pompili S, Ventura L, Dubuquoy C, Speca S, Gaudio E, Latella G, Vetuschi A. Interaction between sphingosine kinase/sphingosine 1 phosphate and transforming growth factor-β/Smads pathways in experimental intestinal fibrosis. An in vivo immunohistochemical study. Eur J Histochem 2018; 62. [PMID: 30064196 PMCID: PMC6077868 DOI: 10.4081/ejh.2018.2956] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 07/19/2018] [Indexed: 02/06/2023] Open
Abstract
A concomitant action of multiple profibrotic mediators appears crucial in the development and progression of fibrosis. Sphingosine kinase/sphingosine 1 phosphate and transforming growth factor- β/Smads pathways are both involved in pathogenesis of fibrosis in several organs by controlling differentiation of fibroblasts to myofibroblasts and the epithelial-to-mesenchymal transition. However, their direct involvement in chronic colitis-associated fibrosis it is not yet known. In this study we evaluated the immunohistochemical expression of some proteins implicated in sphingosine kinase/sphingosine 1 phosphate and transforming growth factor-β/Smads pathways in Dextrane Sodium Sulphate (DSS)- induced colorectal fibrosis in mice. Compared to control mice, DSS-induced chronic colitis mice developed a marked intestinal fibrosis associated with a concomitant overexpression of TGF-β, p-Smad3, α-SMA, collagen I-III, SPHK1, RhoA, PI3K, Akt, p-Akt, p-mTOR. This study highlights the relationship between the two pathways and the possible role of SPHK1 in the intestinal fibrosis. These results, if confirmed by in vitro studies, may have important clinical implications in the development of new therapeutical approaches in inflammatory bowel disease.
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Affiliation(s)
- Roberta Sferra
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila.
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31
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Lian L, Huang Q, Zhang L, Qin H, He X, He X, Ke J, Xie M, Lan P. Anti-fibrogenic Potential of Mesenchymal Stromal Cells in Treating Fibrosis in Crohn's Disease. Dig Dis Sci 2018; 63:1821-1834. [PMID: 29704139 DOI: 10.1007/s10620-018-5082-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Accepted: 04/16/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Intestinal fibrosis is a major complication of CD and may result in stricture formation leading to intestinal obstruction. MSCs play multiple roles in active CD and fibrosis-associated diseases. AIMS This study was designed to investigate the role of MSCs in CD-associated intestinal fibrosis. METHODS Intestinal fibrosis was induced over 7 weeks of enema with increasing doses of TNBS and assessed by Masson's trichrome staining. Transcriptome sequencing and gene set enrichment analysis were conducted to reveal the transcriptome changes among groups at the mRNA level. Immunofluorescence assays were used to validate the role of EMT in intestinal fibrosis. Quantitative real-time PCR and immunohistochemistry analyses were performed to clarify the association between the anti-fibrogenic properties of MSCs and the immune microenvironment. Western blotting was used to verify the potential signaling pathways. RESULTS Fibrotic tissue accumulation and inflammatory cell infiltration were detected in the colon tissue after TNBS induction treatment. Prophylactic MSCs treatment inhibited colon shortening, while therapeutic treatment decreased colon weight. Prophylactic treatment with MSCs inhibited the accumulation of fibrotic tissue, the expression of fibrotic proteins and EMT. Therapeutic MSCs treatment reversed the established intestinal fibrosis and reduced EMT. The secretion of the fibrogenic factors IL-1beta, IL-6 and IL-13 was down-regulated after both MSCs treatment approaches, while IL-10, an anti-fibrogenic factor, was up-regulated. Both MSCs therapies inhibited the expression of TGF-beta and the phosphorylation of Smad2 and Smad3 after TNBS induction. CONCLUSION MSCs exert anti-fibrogenic activity against CD-associated fibrosis by regulating the inflammatory environment, inhibiting the TGF-beta/Smad signaling pathway and ameliorating EMT.
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Affiliation(s)
- Lei Lian
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, China. .,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Qunsheng Huang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Longjuan Zhang
- Laboratory of Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Huabo Qin
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, China.,Department of General and Pediatric Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Xiaosheng He
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xin He
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, China.,Department of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou City, Guangdong, China
| | - Jia Ke
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Minghao Xie
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, China.,Department of General Surgery, The Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, China
| | - Ping Lan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, 510655, Guangdong, China. .,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
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Huang SY, Li XH, Huang L, Sun CH, Fang ZN, Zhang MC, Lin JJ, Jiang MJ, Mao R, Li ZP, Zhang Z, Feng ST. T2* Mapping to characterize intestinal fibrosis in crohn's disease. J Magn Reson Imaging 2018; 48:829-836. [PMID: 29663577 DOI: 10.1002/jmri.26022] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 03/02/2018] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Assessing bowel fibrosis in patients with Crohn's disease (CD) has important therapeutic implications. PURPOSE To determine the utility of T2* mapping versus that of contrast enhanced (CE) imaging in grading intestinal fibrosis in patients with CD using surgical pathology as the reference standard. STUDY TYPE Prospective. SPECIMENS 102 specimens from 27 patients with CD. FIELD STRENGTH/SEQUENCE 3.0T; T2WI; T1WI; T2*WI. ASSESSMENT The T2*WI values of the bowel wall targeted for resection were measured by two radiologists by drawing regions of interest on the thickened bowel wall. The resected bowel specimens with pathological fibrosis and type I collagen were classified into four severity grades (0-3) by a pathologist using a semi-quantitative scoring system. STATISTICAL TESTS The differences in the T2*WI values among the different histological grades were analyzed using one-way analysis of variance or the Kruskal-Wallis test, and their correlations were analyzed. The ability of the T2*WI values to discriminate between various degrees of fibrosis was assessed using a receiver operating characteristic (ROC) curve. RESULTS Significant differences were observed in the T2* values of mild (23.56 ± 1.60 ms), moderate (16.19 ± 0.55 ms), and severe (13.59 ± 0.53 ms) fibrosis types (F = 35.84; P < 0.001). T2* values were moderately associated with histological fibrosis (r = -0.627; P < 0.001) and type I collagen scores (r = -0.588; P < 0.001). T2* values were highly accurate, with an area under the ROC curve (AUC) of 0.951 (P < 0.001) for differentiating moderate-to-severe fibrosis from nonfibrosis and mild fibrosis, followed by an AUC of 0.508 for the percentage of enhancement gain (P = 0.908). A threshold T2* value of 18.06 ms was recommended for diagnosing moderate-to-severe fibrosis with 94.7% sensitivity and 78.3% specificity. DATA CONCLUSION MRI T2* mapping outperforms CE parameters in distinction of various degrees of bowel fibrosis in CD. LEVEL OF EVIDENCE 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.
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Affiliation(s)
- Si-Yun Huang
- Department of Radiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Xue-Hua Li
- Department of Radiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Li Huang
- Department of Radiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Can-Hui Sun
- Department of Radiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Zhuang-Nian Fang
- Department of Radiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Meng-Chen Zhang
- Department of Radiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Jin-Jiang Lin
- Department of Radiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Meng-Jie Jiang
- Department of Radiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
- Department of Radiology, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Zi-Ping Li
- Department of Radiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
| | - Zhongwei Zhang
- Department of Radiology, University of Florida, Gainesville, Florida, USA
| | - Shi-Ting Feng
- Department of Radiology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
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Wei Y, Zhu F, Gong J, Yang J, Zhang T, Gu L, Zhu W, Guo Z, Li Y, Li N, Li J. High Visceral to Subcutaneous Fat Ratio Is Associated with Increased Postoperative Inflammatory Response after Colorectal Resection in Inflammatory Bowel Disease. Gastroenterol Res Pract 2018; 2018:6270514. [PMID: 29849595 PMCID: PMC5903301 DOI: 10.1155/2018/6270514] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 12/16/2017] [Accepted: 01/22/2018] [Indexed: 02/07/2023] Open
Abstract
AIM Excessive postoperative inflammatory response, which is characterized by overproduction of cytokines, often leads to complications after colorectal surgery. However, the impact of body composition on postoperative inflammatory response is largely unknown. The aim of this study is to elucidate whether body fat amount and its distribution affects postoperative inflammation after colorectal surgery in IBD patients. METHODS Eighty-six patients undergoing colorectal resection for IBD from June 2014 to Jan 2017 were enrolled. Abdominal CT images within one week prior to surgery were assessed for visceral fat, subcutaneous fat, and muscle mass. Postoperative inflammatory response was evaluated using serum CRP, PCT, and IL-6 levels on postoperative days 1, 3, and 5. Univariate analysis was conducted to identify risk factors for infectious complications. The correlation between body composition and postoperative plasma concentration of inflammatory markers was analyzed using a linear regression model. ROC curve was applied to analyze the effect of different body composition parameters on postoperative infectious complications and to determine the relationship between inflammatory markers and infectious complications. RESULTS Neither volume of fat or muscle was related to postoperative plasma concentrations of CRP, IL-6, and PCT. However, visceral to subcutaneous fat ratio was associated with PCT levels on postoperative days (POD) 1, 3, and 5, with the highest regression coefficient on POD1 (β = 0.360; 95% CI, 0.089-0.631; P = 0.010). Body composition did not predict postoperative infectious complications, while CRP on POD 3 was predictive of infectious complications. CONCLUSION Increased visceral to subcutaneous fat ratio was associated with postoperative inflammatory response in IBD patients undergoing colorectal resection. This may partly explain the increased incidence of postoperative complications in patients with visceral obesity.
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Affiliation(s)
- Yao Wei
- Department of Emergency and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Pinghai Road 900, Suzhou 215031, China
| | - Feng Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, East Zhongshan Road 305, Nanjing 210002, China
| | - Jianfeng Gong
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, East Zhongshan Road 305, Nanjing 210002, China
| | - Jianbo Yang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, East Zhongshan Road 305, Nanjing 210002, China
| | - Tenghui Zhang
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, East Zhongshan Road 305, Nanjing 210002, China
| | - Lili Gu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, East Zhongshan Road 305, Nanjing 210002, China
| | - Weiming Zhu
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, East Zhongshan Road 305, Nanjing 210002, China
| | - Zhen Guo
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, East Zhongshan Road 305, Nanjing 210002, China
| | - Yi Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, East Zhongshan Road 305, Nanjing 210002, China
| | - Ning Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, East Zhongshan Road 305, Nanjing 210002, China
| | - Jieshou Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, East Zhongshan Road 305, Nanjing 210002, China
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Li XH, Mao R, Huang SY, Sun CH, Cao QH, Fang ZN, Zhang ZW, Huang L, Lin JJ, Chen YJ, Rimola J, Rieder F, Chen MH, Feng ST, Li ZP. Characterization of Degree of Intestinal Fibrosis in Patients with Crohn Disease by Using Magnetization Transfer MR Imaging. Radiology 2018; 287:494-503. [PMID: 29357272 DOI: 10.1148/radiol.2017171221] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Purpose To evaluate the role of magnetization transfer (MT) magnetic resonance (MR) imaging for the characterization of intestinal fibrosis compared with contrast material-enhanced and diffusion-weighted MR imaging and its capability for differentiating fibrotic from inflammatory strictures in humans with Crohn disease (CD) by using surgical histopathologic analysis as the reference standard. Materials and Methods Institutional review board approval and informed consent were obtained for this prospective study. Abdominal MT imaging, contrast-enhanced imaging, and diffusion-weighted imaging of 31 consecutive patients with CD were analyzed before elective surgery. The bowel wall MT ratio normalized to skeletal muscle, the apparent diffusion coefficient (ADC), and the percentage of enhancement gain were calculated; region-by-region correlations with the surgical specimen were performed to determine the histologic degree of fibrosis and inflammation. The performance of MT imaging was validated in five new patients. One-way analysis of variance test, Spearman rank correlation, and receiver operating characteristic curve were used for statistical analysis. Results Normalized MT ratios strongly correlated with fibrosis scores (r = 0.769; P = .000) but did not correlate with inflammation scores (r = -0.034; P = .740). Significant differences (F = 49.002; P = .000) in normalized MT ratios were found among nonfibrotic, mildly, moderately, and severely fibrotic walls. The normalized MT ratios of mixed fibrotic and inflammatory bowel walls were significantly higher than those of bowel walls with only inflammation present (t = -8.52; P = .000). A high accuracy of normalized MT ratios was shown with an area under the receiver operating characteristic curve (AUC) of 0.919 (P = .000) for differentiating moderately to severely fibrotic bowel walls from nonfibrotic and mildly fibrotic bowel walls, followed by ADC (AUC, 0.747; P = .001) and the percentage of enhancement gain (AUC, 0.592; P = .209). The sensitivity, specificity, and AUC of MT imaging for diagnosing moderate to severe fibrosis in the validation data set were 80% (12 of 15), 100% (three of three), and 0.9 (P = .033), respectively. Conclusion MT imaging outperforms ADC and contrast-enhanced imaging in detecting and distinguishing varying degrees of bowel fibrosis with or without coexisting inflammation. MT imaging could potentially be used as a method to differentiate fibrotic from inflammatory intestinal strictures in patients with CD. © RSNA, 2018 Online supplemental material is available for this article.
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Affiliation(s)
- Xue-Hua Li
- From the Departments of Radiology (X.H.L., S.Y.H., C.H.S., Z.N.F., L.H., J.J.L., S.T.F., Z.P.L.), Gastroenterology (R.M., M.H.C.), Pathology (Q.H.C.), and Ultrasound (Y.J.C.), The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou 510080, People's Republic of China; Department of Biomedical Engineering, Cancer Biology and Radiology, Wake Forest School of Medicine, Winston-Salem, NC (Z.W.Z.); Department of Radiology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain (J.R.); and Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio (F.R.)
| | - Ren Mao
- From the Departments of Radiology (X.H.L., S.Y.H., C.H.S., Z.N.F., L.H., J.J.L., S.T.F., Z.P.L.), Gastroenterology (R.M., M.H.C.), Pathology (Q.H.C.), and Ultrasound (Y.J.C.), The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou 510080, People's Republic of China; Department of Biomedical Engineering, Cancer Biology and Radiology, Wake Forest School of Medicine, Winston-Salem, NC (Z.W.Z.); Department of Radiology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain (J.R.); and Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio (F.R.)
| | - Si-Yun Huang
- From the Departments of Radiology (X.H.L., S.Y.H., C.H.S., Z.N.F., L.H., J.J.L., S.T.F., Z.P.L.), Gastroenterology (R.M., M.H.C.), Pathology (Q.H.C.), and Ultrasound (Y.J.C.), The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou 510080, People's Republic of China; Department of Biomedical Engineering, Cancer Biology and Radiology, Wake Forest School of Medicine, Winston-Salem, NC (Z.W.Z.); Department of Radiology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain (J.R.); and Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio (F.R.)
| | - Can-Hui Sun
- From the Departments of Radiology (X.H.L., S.Y.H., C.H.S., Z.N.F., L.H., J.J.L., S.T.F., Z.P.L.), Gastroenterology (R.M., M.H.C.), Pathology (Q.H.C.), and Ultrasound (Y.J.C.), The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou 510080, People's Republic of China; Department of Biomedical Engineering, Cancer Biology and Radiology, Wake Forest School of Medicine, Winston-Salem, NC (Z.W.Z.); Department of Radiology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain (J.R.); and Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio (F.R.)
| | - Qing-Hua Cao
- From the Departments of Radiology (X.H.L., S.Y.H., C.H.S., Z.N.F., L.H., J.J.L., S.T.F., Z.P.L.), Gastroenterology (R.M., M.H.C.), Pathology (Q.H.C.), and Ultrasound (Y.J.C.), The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou 510080, People's Republic of China; Department of Biomedical Engineering, Cancer Biology and Radiology, Wake Forest School of Medicine, Winston-Salem, NC (Z.W.Z.); Department of Radiology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain (J.R.); and Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio (F.R.)
| | - Zhuang-Nian Fang
- From the Departments of Radiology (X.H.L., S.Y.H., C.H.S., Z.N.F., L.H., J.J.L., S.T.F., Z.P.L.), Gastroenterology (R.M., M.H.C.), Pathology (Q.H.C.), and Ultrasound (Y.J.C.), The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou 510080, People's Republic of China; Department of Biomedical Engineering, Cancer Biology and Radiology, Wake Forest School of Medicine, Winston-Salem, NC (Z.W.Z.); Department of Radiology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain (J.R.); and Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio (F.R.)
| | - Zhong-Wei Zhang
- From the Departments of Radiology (X.H.L., S.Y.H., C.H.S., Z.N.F., L.H., J.J.L., S.T.F., Z.P.L.), Gastroenterology (R.M., M.H.C.), Pathology (Q.H.C.), and Ultrasound (Y.J.C.), The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou 510080, People's Republic of China; Department of Biomedical Engineering, Cancer Biology and Radiology, Wake Forest School of Medicine, Winston-Salem, NC (Z.W.Z.); Department of Radiology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain (J.R.); and Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio (F.R.)
| | - Li Huang
- From the Departments of Radiology (X.H.L., S.Y.H., C.H.S., Z.N.F., L.H., J.J.L., S.T.F., Z.P.L.), Gastroenterology (R.M., M.H.C.), Pathology (Q.H.C.), and Ultrasound (Y.J.C.), The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou 510080, People's Republic of China; Department of Biomedical Engineering, Cancer Biology and Radiology, Wake Forest School of Medicine, Winston-Salem, NC (Z.W.Z.); Department of Radiology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain (J.R.); and Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio (F.R.)
| | - Jin-Jiang Lin
- From the Departments of Radiology (X.H.L., S.Y.H., C.H.S., Z.N.F., L.H., J.J.L., S.T.F., Z.P.L.), Gastroenterology (R.M., M.H.C.), Pathology (Q.H.C.), and Ultrasound (Y.J.C.), The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou 510080, People's Republic of China; Department of Biomedical Engineering, Cancer Biology and Radiology, Wake Forest School of Medicine, Winston-Salem, NC (Z.W.Z.); Department of Radiology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain (J.R.); and Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio (F.R.)
| | - Yu-Jun Chen
- From the Departments of Radiology (X.H.L., S.Y.H., C.H.S., Z.N.F., L.H., J.J.L., S.T.F., Z.P.L.), Gastroenterology (R.M., M.H.C.), Pathology (Q.H.C.), and Ultrasound (Y.J.C.), The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou 510080, People's Republic of China; Department of Biomedical Engineering, Cancer Biology and Radiology, Wake Forest School of Medicine, Winston-Salem, NC (Z.W.Z.); Department of Radiology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain (J.R.); and Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio (F.R.)
| | - Jordi Rimola
- From the Departments of Radiology (X.H.L., S.Y.H., C.H.S., Z.N.F., L.H., J.J.L., S.T.F., Z.P.L.), Gastroenterology (R.M., M.H.C.), Pathology (Q.H.C.), and Ultrasound (Y.J.C.), The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou 510080, People's Republic of China; Department of Biomedical Engineering, Cancer Biology and Radiology, Wake Forest School of Medicine, Winston-Salem, NC (Z.W.Z.); Department of Radiology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain (J.R.); and Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio (F.R.)
| | - Florian Rieder
- From the Departments of Radiology (X.H.L., S.Y.H., C.H.S., Z.N.F., L.H., J.J.L., S.T.F., Z.P.L.), Gastroenterology (R.M., M.H.C.), Pathology (Q.H.C.), and Ultrasound (Y.J.C.), The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou 510080, People's Republic of China; Department of Biomedical Engineering, Cancer Biology and Radiology, Wake Forest School of Medicine, Winston-Salem, NC (Z.W.Z.); Department of Radiology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain (J.R.); and Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio (F.R.)
| | - Min-Hu Chen
- From the Departments of Radiology (X.H.L., S.Y.H., C.H.S., Z.N.F., L.H., J.J.L., S.T.F., Z.P.L.), Gastroenterology (R.M., M.H.C.), Pathology (Q.H.C.), and Ultrasound (Y.J.C.), The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou 510080, People's Republic of China; Department of Biomedical Engineering, Cancer Biology and Radiology, Wake Forest School of Medicine, Winston-Salem, NC (Z.W.Z.); Department of Radiology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain (J.R.); and Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio (F.R.)
| | - Shi-Ting Feng
- From the Departments of Radiology (X.H.L., S.Y.H., C.H.S., Z.N.F., L.H., J.J.L., S.T.F., Z.P.L.), Gastroenterology (R.M., M.H.C.), Pathology (Q.H.C.), and Ultrasound (Y.J.C.), The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou 510080, People's Republic of China; Department of Biomedical Engineering, Cancer Biology and Radiology, Wake Forest School of Medicine, Winston-Salem, NC (Z.W.Z.); Department of Radiology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain (J.R.); and Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio (F.R.)
| | - Zi-Ping Li
- From the Departments of Radiology (X.H.L., S.Y.H., C.H.S., Z.N.F., L.H., J.J.L., S.T.F., Z.P.L.), Gastroenterology (R.M., M.H.C.), Pathology (Q.H.C.), and Ultrasound (Y.J.C.), The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou 510080, People's Republic of China; Department of Biomedical Engineering, Cancer Biology and Radiology, Wake Forest School of Medicine, Winston-Salem, NC (Z.W.Z.); Department of Radiology, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain (J.R.); and Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio (F.R.)
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Yang J, Zhou CZ, Zhu R, Fan H, Liu XX, Duan XY, Tang Q, Shou ZX, Zuo DM. miR-200b-containing microvesicles attenuate experimental colitis associated intestinal fibrosis by inhibiting epithelial-mesenchymal transition. J Gastroenterol Hepatol 2017; 32:1966-1974. [PMID: 28370348 DOI: 10.1111/jgh.13797] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Revised: 03/06/2017] [Accepted: 03/28/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Epithelial-mesenchymal transition (EMT), characterized by the decrease of E-cadherin (E-Cad) and increase in vimentin and alpha-smooth muscle actin (α-SMA), was demonstrated to participate in inflammatory bowel disease-related fibrosis. miR-200b plays an anti-fibrosis role in inhibiting EMT by targeting ZEB1 and ZEB2. But the stability of exogenous miR-200b in blood limits its application. Microvesicles (MVs), which can transfer miRNAs among cells and prevent them from degradation, may provide an excellent transport system for the delivery of miR-200b in the treatment of fibrosis. METHODS Bone marrow mesenchymal stem cells (BMSCs) were transfected with lentivirus to overexpress miR-200b. The MVs packaged with miRNA-200b were harvested for the anti-fibrotic treatment using in vitro (transforming growth factor beta 1-mediated EMT in intestinal epithelial cells: IEC-6) and in vivo (TNBS-induced intestinal fibrosis in rats) models. The pathological morphology was observed, and the fibrosis related proteins, such as E-Cad, vimentin, α-SMA, ZEB1, and ZEB2, were detected. RESULTS MiR-200b-MVs would significantly reverse the morphology in TGF-β1-treated IEC-6 cells and improve the TNBS-induced colon fibrosis histologically. The treatment of miR-200b-MVs increased miR-200b levels both in the IEC-6 cells and colon, resulting in a significant prevention EMT and alleviation of fibrosis. The expression of E-Cad was increased, and the expressions of vimentin and α-SMA were decreased. ZBE1 and ZEB2, the targets of miR-200b, were also decreased. CONCLUSIONS miR-200b could be transferred from genetically modified BMSCs to the target cells or tissue by MVs. The mechanisms of miR-200b-MVs in inhibiting colonic fibrosis were related to suppressing the development of EMT by targeting ZEB1and ZEB2.
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Affiliation(s)
- Jia Yang
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cheng-Zhi Zhou
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Cardiology, The Affiliated Hospital of Hubei University of Traditional Chinese Medicine, Wuhan, China
| | - Rui Zhu
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Heng Fan
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xing-Xing Liu
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xue-Yun Duan
- Department of Pharmacy, The Affiliated Hospital of Hubei University of Traditional Chinese Medicine, Wuhan, China
| | - Qing Tang
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhe-Xing Shou
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dong-Mei Zuo
- Department of Integrated Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Dai M, Jin L, Xu WT, Xiong YM, Wang YM, Zheng GR. Effect of TGF-β 1 neutralizing antibody on intestinal fibrosis in a mouse model of chronic colitis induced with trinitrobenzene sulfonic acid. Shijie Huaren Xiaohua Zazhi 2017; 25:783-791. [DOI: 10.11569/wcjd.v25.i9.783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the effect of transforming growth factor-β1 (TGF-β1) neutralizing antibody on intestinal fibrosis in a mouse model of chronic colitisinduced with trinitrobenzene sulfonic acid (TNBS).
METHODS Forty-eight Balb/c mice were randomly divided into a normal control group, a model control group, a treatment control group, and a TGF-β1 antibody group. Chronic colitis and intestinal fibrosis were induced with TNBS/ethanol enema for 6 wk. Mice in the TGF-β1 antibody group and treatment control group were administered with TGF-β1 neutralizing antibody and physiological saline, respectively, at 24 h after the administration of TNBS/ethanol enema. The pathological changes in intestine tissue were detected by HE and VG collage staining. Expression of TGF-β1 and collagen types Ⅰ, Ⅲ, and Ⅴ mRNAs in the colon was detected.
RESULTS HE and VG collage staining showed that pathologic histology was improved in the TGF-β1 antibody group. The expression of collagen types Ⅰ, Ⅲ, and Ⅴ and TGF-β1 mRNAs decreased significantly in the TGF-β1 antibody group compared with the model control group and the treatment control group (P < 0.05). The protein expression of TGF-β1 also decreased significantly in the TGF-β1 antibody group compared with the model control group and the treatment control group (P < 0.05).
CONCLUSION TGF-β1 neutralizing antibody can effectively down-regulate the expression of TGF-β1 and collagen in mice with chronic colitis, and intestinal fibrosis can be abrogated by targeting TGF-β1.
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Di Gregorio J, Sferra R, Speca S, Vetuschi A, Dubuquoy C, Desreumaux P, Pompili S, Cristiano L, Gaudio E, Flati V, Latella G. Role of glycogen synthase kinase-3β and PPAR-γ on epithelial-to-mesenchymal transition in DSS-induced colorectal fibrosis. PLoS One 2017; 12:e0171093. [PMID: 28207769 PMCID: PMC5313173 DOI: 10.1371/journal.pone.0171093] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 01/15/2017] [Indexed: 02/07/2023] Open
Abstract
Background Intestinal fibrosis is characterized by abnormal production and deposition of extracellular matrix (ECM) proteins by activated myofibroblasts. The main progenitor cells of activated myofibroblasts are the fibroblasts and the epithelial cells, the latter through the epithelial-mesenchymal transition (EMT). Aim To evaluate the action of the new PPAR-γ modulator, GED-0507-34 Levo (GED) on the expression of EMT associated and regulatory proteins such as TGF-β, Smad3, E-cadherin, Snail, ZEB1, β-catenin, and GSK-3β, in a mouse model of DSS-induced intestinal fibrosis. Methods Chronic colitis and fibrosis were induced by oral administration of 2.5% DSS (w/v) for 6 weeks. GW9662 (GW), a selective PPAR-γ inhibitor, was also administered by intraperitoneal injection at the dose of 1 mg/kg/day combined with GED treatment. All drugs were administered at the beginning of the second cycle of DSS (day 12). 65 mice were randomly divided into five groups (H2O as controls n = 10, H2O+GED n = 10, DSS n = 15, DSS+GED n = 15, DSS+GED+GW n = 15). The colon was excised for macroscopic examination and histological and morphometric analyses. The level of expression of molecules involved in EMT and fibrosis, like TGF-β, Smad3, E-cadherin, Snail, ZEB1, β-catenin, GSK-3β and PPAR-γ, was assessed by immunohistochemistry, immunofluorescence, western blot and Real Time PCR. Results GED improved the DSS-induced chronic colitis and fibrosis. GED was able to reduce the expression of the main fibrosis markers (α-SMA, collagen I-III and fibronectin) as well as the pivotal pro-fibrotic molecules IL-13, TGF-β and Smad3, while it increased the anti-fibrotic PPAR-γ. All these GED effects were nullified by co-administration of GW with GED. Furthermore, GED was able to normalize the expression levels of E-cadherin and β-catenin and upregulated GSK-3β, that are all known to be involved both in EMT and fibrosis. Conclusions The DSS-induced intestinal fibrosis was improved by the new PPAR-γ modulator GED-0507-34 Levo through the modulation of EMT mediators and pro-fibrotic molecules and through GSK-3β induction.
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Affiliation(s)
- Jacopo Di Gregorio
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Roberta Sferra
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Silvia Speca
- University of Lille, U995, Lille Inflammation Research International Center (LIRIC), F-59000 Lille, France
- IBD, Lille, France
| | - Antonella Vetuschi
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
- * E-mail:
| | | | - Pierre Desreumaux
- University of Lille, U995, Lille Inflammation Research International Center (LIRIC), F-59000 Lille, France
- IBD, Lille, France
- CHR Lille, Service des Maladies de l’Appareil Digestif et de la Nutrition, Hôpital Claude Huriez, Lille, France
| | - Simona Pompili
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Loredana Cristiano
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L’Aquila, Italy
| | - Eugenio Gaudio
- Department of Human Anatomy, University of Rome La Sapienza, Rome, Italy
| | - Vincenzo Flati
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - Giovanni Latella
- Department of Life, Health and Environmental Sciences, Gastroenterology Unit, University of L'Aquila, L'Aquila, Italy
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Kadir SI, Wenzel Kragstrup T, Dige A, Kok Jensen S, Dahlerup JF, Kelsen J. Pirfenidone inhibits the proliferation of fibroblasts from patients with active Crohn's disease. Scand J Gastroenterol 2016; 51:1321-5. [PMID: 27181436 DOI: 10.1080/00365521.2016.1185146] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE One-third of Crohn's disease (CD) patients develop intestinal strictures that require repeated surgical intervention. Current anti-inflammatory therapies have limited effect on stricture development, which necessitates the exploration of new pharmacological approaches. Pirfenidone (PFD), a novel anti-fibrotic agent, was recently approved in Europe for the treatment of idiopathic pulmonary fibrosis (IPF). We hypothesized that observations in IPF could be transferable to intestinal fibrosis and that PFD inhibits the proliferation and extracellular matrix (ECM) turnover of gut-derived fibroblasts from CD patients. MATERIAL AND METHODS Fibroblasts were isolated from biopsies of inflamed (n = 8) and non-inflamed (n = 5) colonic mucosa. Expression of CD90 and alpha-smooth muscle actin (αSMA) expression was determined by flow cytometry. The fibroblasts were cultured with PFD (0.5, 1.0 and 2.0 mg/ml). Proliferation was evaluated with CellTiter 96(®) AQueous One Solution Cell Proliferation Assay. Production of matrix metalloproteinase-3 (MMP-3), tissue inhibitor of metalloproteinases-1 (TIMP-1) and collagen were assessed using ELISA and calorimetric assays, respectively. RESULTS The majority of the fibroblasts were αSMA-positive myofibroblasts. PFD inhibited fibroblast proliferation [0.94 (PFD 0.5 mg/ml); 0.76 (1.0 mg/ml); 0.58 (2.0 mg/ml)] and production of MMP-3 [0.85 (0.5 mg/ml); 0.74 (1.0 mg/ml); 0.63 (2.0 mg/ml)] dose-dependently (both p = 0.0001). The anti-proliferative effect of PFD was reversible (p = 0.0001), indicating that PFD does not act by an irreversible cytotoxic mechanism. PFD did not influence neither TIMP-1 nor collagen production. CONCLUSION PFD inhibited the proliferation and the production of MMP-3 dose-dependently in gut-derived fibroblast from CD patients. Our observations support further studies on PFD in stricturing CD.
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Affiliation(s)
- Sara-Irini Kadir
- a Department of Hepatology and Gastroenterology , Gastro-Immuno Research Laboratory (GIRL), Aarhus University Hospital , Aarhus , Denmark
| | | | - Anders Dige
- a Department of Hepatology and Gastroenterology , Gastro-Immuno Research Laboratory (GIRL), Aarhus University Hospital , Aarhus , Denmark
| | - Simon Kok Jensen
- b Department of Biomedicine , Aarhus University , Aarhus , Denmark
| | - Jens Frederik Dahlerup
- a Department of Hepatology and Gastroenterology , Gastro-Immuno Research Laboratory (GIRL), Aarhus University Hospital , Aarhus , Denmark
| | - Jens Kelsen
- a Department of Hepatology and Gastroenterology , Gastro-Immuno Research Laboratory (GIRL), Aarhus University Hospital , Aarhus , Denmark
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Abstract
The cause of Crohn’s disease (CD) has posed a conundrum for at least a century. A large body of work coupled with recent technological advances in genome research have at last started to provide some of the answers. Initially this review seeks to explain and to differentiate between bowel inflammation in the primary immunodeficiencies that generally lead to very early onset diffuse bowel inflammation in humans and in animal models, and the real syndrome of CD. In the latter, a trigger, almost certainly enteric infection by one of a multitude of organisms, allows the faeces access to the tissues, at which stage the response of individuals predisposed to CD is abnormal. Direct investigation of patients’ inflammatory response together with genome-wide association studies (GWAS) and DNA sequencing indicate that in CD the failure of acute inflammation and the clearance of bacteria from the tissues, and from within cells, is defective. The retained faecal products result in the characteristic chronic granulomatous inflammation and adaptive immune response. In this review I will examine the contemporary evidence that has led to this understanding, and look for explanations for the recent dramatic increase in the incidence of this disease.
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Abstract
The cause of Crohn's disease (CD) has posed a conundrum for at least a century. A large body of work coupled with recent technological advances in genome research have at last started to provide some of the answers. Initially this review seeks to explain and to differentiate between bowel inflammation in the primary immunodeficiencies that generally lead to very early onset diffuse bowel inflammation in humans and in animal models, and the real syndrome of CD. In the latter, a trigger, almost certainly enteric infection by one of a multitude of organisms, allows the faeces access to the tissues, at which stage the response of individuals predisposed to CD is abnormal. Direct investigation of patients' inflammatory response together with genome-wide association studies (GWAS) and DNA sequencing indicate that in CD the failure of acute inflammation and the clearance of bacteria from the tissues, and from within cells, is defective. The retained faecal products result in the characteristic chronic granulomatous inflammation and adaptive immune response. In this review I will examine the contemporary evidence that has led to this understanding, and look for explanations for the recent dramatic increase in the incidence of this disease.
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de Bruyn M, Vandooren J, Ugarte-Berzal E, Arijs I, Vermeire S, Opdenakker G. The molecular biology of matrix metalloproteinases and tissue inhibitors of metalloproteinases in inflammatory bowel diseases. Crit Rev Biochem Mol Biol 2016; 51:295-358. [PMID: 27362691 DOI: 10.1080/10409238.2016.1199535] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Talapka P, Berkó A, Nagy LI, Chandrakumar L, Bagyánszki M, Puskás LG, Fekete &E, Bódi N. Structural and molecular features of intestinal strictures in rats with Crohn's-like disease. World J Gastroenterol 2016; 22:5154-5164. [PMID: 27298558 PMCID: PMC4893462 DOI: 10.3748/wjg.v22.i22.5154] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 03/23/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To develop a new rat model we wanted to gain a better understanding of stricture formation in Crohn’s disease (CD).
METHODS: Chronic colitis was induced locally by the administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS). The relapsing inflammation characteristic to CD was mimicked by repeated TNBS treatments. Animals were randomly divided into control, once, twice and three times TNBS-treated groups. Control animals received an enema of saline. Tissue samples were taken from the strictured colonic segments and also adjacent proximally and distally to its 60, 90 or 120 d after the last TNBS or saline administrations. The frequency and macroscopic extent of the strictures were measured on digital photographs. The structural features of strictured gut wall were studied by light- and electron microscopy. Inflammation related alterations in TGF-beta 2 and 3, matrix metalloproteinases 9 (MMP9) and TIMP1 mRNA and protein expression were determined by quantitative real-time PCR and western blot analysis. The quantitative distribution of caspase 9 was determined by post-embedding immunohistochemistry.
RESULTS: Intestinal strictures first appeared 60 d after TNBS treatments and the frequency of them increased up to day 120. From day 90 an intact lamina epithelialis, reversible thickening of lamina muscularis mucosae and irreversible thickening of the muscularis externa were demonstrated in the strictured colonic segments. Nevertheless the morphological signs of apoptosis were frequently seen and excess extracellular matrix deposition was recorded between smooth muscle cells (SMCs). Enhanced caspase 9 expression on day 90 in the SMCs and on day 120 also in myenteric neurons indicated the induction of apoptosis. The mRNA expression profile of TGF-betas after repeated TNBS doses was characteristic to CD, TGF-beta 2, but not TGF-beta 3 was up-regulated. Overexpression of MMP9 and down-regulation of TIMP1 were demonstrated. The progressive increase in the amount of MMP9 protein in the strictures was also obvious between days 90 and 120 but TIMP1 protein was practically undetectable at this time.
CONCLUSION: These findings indicate that aligned structural and molecular changes in the gut wall rather than neuronal cell death play the primary role in stricture formation.
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Roulis M, Flavell RA. Fibroblasts and myofibroblasts of the intestinal lamina propria in physiology and disease. Differentiation 2016; 92:116-131. [PMID: 27165847 DOI: 10.1016/j.diff.2016.05.002] [Citation(s) in RCA: 131] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 04/19/2016] [Accepted: 05/03/2016] [Indexed: 01/14/2023]
Abstract
In this Review we summarize our current understanding of the biology of mesenchymal cells of the intestinal lamina propria focusing mainly on fibroblasts and myofibroblasts. The topics covered include 1) the embryonic origin of mesenchymal cells of the intestinal lamina propria and their heterogeneity in adults, 2) the role of the mesenchyme in intestinal development, 3) the physiological function of fibroblasts and myofibroblasts in adults as part of the intestinal stem cell niche and the mucosal immune system and 4) the involvement of fibroblasts and myofibroblasts in epithelial homeostasis upon injury and in the pathogenesis of diseases such as Inflammatory Bowel Diseases, fibrosis and cancer. We emphasize studies addressing the function of intestinal mesenchymal cells in vivo, and also discuss major open questions and current challenges in this field.
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Affiliation(s)
- Manolis Roulis
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Richard A Flavell
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
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Body fat composition assessment using analytic morphomics predicts infectious complications after bowel resection in Crohn's disease. Inflamm Bowel Dis 2015; 21:1306-13. [PMID: 25822011 PMCID: PMC4437863 DOI: 10.1097/mib.0000000000000360] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Decisions between medical and surgical management of Crohn's disease (CD) incorporate risk assessments for potential complications of each therapy. Analytic morphomics is a novel method of image analysis providing quantifiable measurements of body tissue composition, characterizing body fat more comprehensively than body mass index alone. The aim of this study was to determine the risk factors associated with postoperative complications in CD, incorporating fat composition analysis using analytic morphomics. METHODS We performed a retrospective review of adults undergoing bowel resection for CD between 2004 and 2011 at a single center. Computed tomography obtained within 30 days prior to surgery underwent morphomic analysis for fat characterization. Postoperative infectious complications were defined as the need for a postoperative abdominal drain, intravenous antibiotics, or reoperation within 30 days. Bivariate and multivariate analyses using logistic regression were used to generate a prediction model of infectious complications. RESULTS A total of 269 subjects met selection criteria; 27% incurred postoperative infectious complications. Bivariate analysis showed hemoglobin, albumin, surgical urgency, high-dose prednisone use, and subcutaneous-to-visceral fat volume distribution as predictors of complications. Body mass index, anti-tumor necrosis factor alpha therapies, and immunomodulator use were not predictors of complication. Multivariate modeling demonstrated a c-statistic of 0.77 and a negative predictive value of 81.1% with surgical urgency (odds ratio = 2.78; 95% confidence interval, 1.46-6.02; P = 0.004), subcutaneous-to-visceral fat distribution (odds ratio = 2.01; 95% confidence interval, 1.20-3.19; P = 0.006), and hemoglobin (odds ratio = 0.69; 95% confidence interval, 0.55-0.85; P = 0.001) as predictors of infectious complication. CONCLUSIONS Fat subtype and distribution are predictive of postoperative infectious complications after bowel resection for CD. Analytic morphomics provides additional body composition detail not captured by body mass index.
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Tao Q, Wang B, Zheng Y, Li G, Ren J. Triptolide ameliorates colonic fibrosis in an experimental rat model. Mol Med Rep 2015; 12:1891-7. [PMID: 25845760 PMCID: PMC4464197 DOI: 10.3892/mmr.2015.3582] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Accepted: 03/12/2015] [Indexed: 12/18/2022] Open
Abstract
Triptolide is known to exert anti-inflammatory and immunomodulatory activities; however, its impact on intestinal fibrosis has not been previously examined. Based on our previous studies of the suppressive activity of triptolide on human colonic subepithelial myofibroblasts and the therapeutic efficacy of triptolide in Crohn's disease, it was hypothesized that triptolide may have beneficial effects on intestinal fibrosis. In the present study, colonic fibrosis was induced in rats by 6 weekly repeated administration with a low-dose of 2,4,6-trinitrobenzene sulfonic acid (TNBS) and was then treated with triptolide or PBS daily (control) simultaneously. Extracellular matrix (ECM) deposition in the colon was examined with image analysis of Masson Trichrome staining. Total collagen levels in colonic homogenates were measured by a Sircol assay. Collagen Iα1 transcripts and collagen I protein were measured ex vivo in the isolated colonic subepithelial myofibroblasts by reverse transcription-quantitative polymerase chain reaction and immunoblot analysis, respectively. The results indicated that triptolide decreased ECM deposition and collagen production in the colon, and inhibited collagen Iα1 transcripts and collagen I protein expression in the isolated subepithelial myofibroblasts of the rats with colonic fibrosis. In conclusion, triptolide ameliorates colonic fibrosis in the experimental rat model, suggesting triptolide may be a promising compound for inflammatory bowel disease treatment.
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Affiliation(s)
- Qingsong Tao
- Department of Surgery, Affiliated Zhongda Hospital, Southeast University Medical School, Nanjing, Jiangsu 210089, P.R. China
| | - Baochai Wang
- Department of Surgery, Affiliated Zhongda Hospital, Southeast University Medical School, Nanjing, Jiangsu 210089, P.R. China
| | - Yu Zheng
- Department of Surgery, Affiliated Zhongda Hospital, Southeast University Medical School, Nanjing, Jiangsu 210089, P.R. China
| | - Guanwei Li
- Department of Surgery, Research Institute of General Surgery, Jinling Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210093, P.R. China
| | - Jianan Ren
- Department of Surgery, Research Institute of General Surgery, Jinling Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210093, P.R. China
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Chang CW, Wong JM, Tung CC, Shih IL, Wang HY, Wei SC. Intestinal stricture in Crohn's disease. Intest Res 2015; 13:19-26. [PMID: 25691840 PMCID: PMC4316217 DOI: 10.5217/ir.2015.13.1.19] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Revised: 09/15/2014] [Accepted: 09/17/2014] [Indexed: 12/13/2022] Open
Abstract
Crohn's disease (CD) is a disease with chronic inflammation of unknown etiology involving any part of the gastrointestinal tract. The incidence and prevalence of CD are increasing recently in Asia. Half of the CD patients will have intestinal complications, such as strictures or fistulas, within 20 years after diagnosis. Twenty-five percentage of CD patients have had at least one small bowel stricture and 10% have had at least one colonic stricture and lead to significant complications. Most of these patients will require at least one surgery during their lifetime. Early diagnosis and evaluation with adequate managements for the patients can prevent disability and mortality of these patient. Here, we reviewed the current incidence of CD with stricture, the etiology of stricture, and how to diagnose and manage the stricture.
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Affiliation(s)
- Chen-Wang Chang
- Department of Gastroenterology, Mackay Memorial Hospital, Taipei; Mackay Junior College of Medicine, Nursing and Management, Taipei; Mackay Medical College, New Taipei, Taiwan
| | - Jau-Min Wong
- Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Chien-Chih Tung
- Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - I-Lun Shih
- Department of Medical Imaging, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Horng-Yuan Wang
- Department of Gastroenterology, Mackay Memorial Hospital, Taipei; Mackay Junior College of Medicine, Nursing and Management, Taipei; Mackay Medical College, New Taipei, Taiwan
| | - Shu-Chen Wei
- Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
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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: 136] [Impact Index Per Article: 13.6] [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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M'Koma AE. Diagnosis of inflammatory bowel disease: Potential role of molecular biometrics. World J Gastrointest Surg 2014. [PMID: 25429322 DOI: 10.4240/wjgs.v6.i11.20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Accurate diagnosis of predominantly colonic inflammatory bowel disease (IBD) is not possible in 30% of patients. For decades, scientists have worked to find a solution to improve diagnostic accuracy for IBD, encompassing Crohn's colitis and ulcerative colitis. Evaluating protein patterns in surgical pathology colectomy specimens of colonic mucosal and submucosal compartments, individually, has potential for diagnostic medicine by identifying integrally independent, phenotype-specific cellular and molecular characteristics. Mass spectrometry (MS) and imaging (I) MS are analytical technologies that directly measure molecular species in clinical specimens, contributing to the in-depth understanding of biological molecules. The biometric-system complexity and functional diversity is well suited to proteomic and diagnostic studies. The direct analysis of cells and tissues by Matrix-Assisted-Laser Desorption/Ionization (MALDI) MS/IMS has relevant medical diagnostic potential. MALDI-MS/IMS detection generates molecular signatures obtained from specific cell types within tissue sections. Herein discussed is a perspective on the use of MALDI-MS/IMS and bioinformatics technologies for detection of molecular-biometric patterns and identification of differentiating proteins. I also discuss a perspective on the global challenge of transferring technologies to clinical laboratories dealing with IBD issues. The significance of serologic-immunometric advances is also discussed.
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Affiliation(s)
- Amosy E M'Koma
- Amosy E M'Koma, Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, TN 37208-3599, United States
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M’Koma AE. Diagnosis of inflammatory bowel disease: Potential role of molecular biometrics. World J Gastrointest Surg 2014; 6:208-219. [PMID: 25429322 PMCID: PMC4241488 DOI: 10.4240/wjgs.v6.i11.208] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 10/16/2014] [Accepted: 10/23/2014] [Indexed: 02/06/2023] Open
Abstract
Accurate diagnosis of predominantly colonic inflammatory bowel disease (IBD) is not possible in 30% of patients. For decades, scientists have worked to find a solution to improve diagnostic accuracy for IBD, encompassing Crohn's colitis and ulcerative colitis. Evaluating protein patterns in surgical pathology colectomy specimens of colonic mucosal and submucosal compartments, individually, has potential for diagnostic medicine by identifying integrally independent, phenotype-specific cellular and molecular characteristics. Mass spectrometry (MS) and imaging (I) MS are analytical technologies that directly measure molecular species in clinical specimens, contributing to the in-depth understanding of biological molecules. The biometric-system complexity and functional diversity is well suited to proteomic and diagnostic studies. The direct analysis of cells and tissues by Matrix-Assisted-Laser Desorption/Ionization (MALDI) MS/IMS has relevant medical diagnostic potential. MALDI-MS/IMS detection generates molecular signatures obtained from specific cell types within tissue sections. Herein discussed is a perspective on the use of MALDI-MS/IMS and bioinformatics technologies for detection of molecular-biometric patterns and identification of differentiating proteins. I also discuss a perspective on the global challenge of transferring technologies to clinical laboratories dealing with IBD issues. The significance of serologic-immunometric advances is also discussed.
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Abstract
The clinical course of inflammatory bowel disease (IBD) is highly heterogeneous and often unpredictable, with multiple and serious complications that range from stricture formation to bowel obstruction or perforation, fistula formation and the need for surgery. All these problems are manifestations of tissue remodeling, a secondary but universal response to the insults of chronic inflammation. The factors involved in tissue remodeling are several, including the site and duration of inflammation, soluble molecules, the gut microbiota, and the type of mesenchymal cell response. The prototypical and most common type of tissue remodeling in IBD, and Crohn's disease (CD) in particular, is a fibrotic response, and this review will focus on the factors and mechanisms involved in fibrogenesis, and speculate on what is needed for the development of a rational treatment of intestinal fibrosis.
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Affiliation(s)
- Florian Rieder
- Department of Pathobiology, Lerner Research Institute, and Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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