The Experts below are selected from a list of 7413 Experts worldwide ranked by ideXlab platform
Peter D.r. Higgins - One of the best experts on this subject based on the ideXlab platform.
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AXL Is a Potential Target for the Treatment of Intestinal Fibrosis.
Inflammatory bowel diseases, 2020Co-Authors: Calen A. Steiner, Eva S. Rodansky, Laura A. Johnson, Jeffrey A Berinstein, Kelly C. Cushing, Sha Huang, Jason R. Spence, Peter D.r. HigginsAbstract:Background Fibrosis is the final common pathway to Intestinal failure in Crohn's disease, but no medical therapies exist to treat Intestinal Fibrosis. Activated myofibroblasts are key effector cells of Fibrosis in multiple organ systems, including the intestine. AXL is a receptor tyrosine kinase that has been implicated in fibrogenic pathways involving myofibroblast activation. We aimed to investigate the AXL pathway as a potential target for the treatment of Intestinal Fibrosis. Methods To establish proof of concept, we first analyzed AXL gene expression in 2 in vivo models of Intestinal Fibrosis and 3 in vitro models of Intestinal Fibrosis. We then tested whether pharmacological inhibition of AXL signaling could reduce fibrogenesis in 3 in vitro models of Intestinal Fibrosis. In vitro testing included 2 distinct cell culture models of Intestinal Fibrosis (matrix stiffness and TGF-β1 treatment) and a human Intestinal organoid model using TGF-β1 cytokine stimulation. Results Our findings suggest that the AXL pathway is induced in models of Intestinal Fibrosis. We demonstrate that inhibition of AXL signaling with the small molecule inhibitor BGB324 abrogates both matrix-stiffness and transforming growth factor beta (TGF-β1)-induced fibrogenesis in human colonic myofibroblasts. AXL inhibition with BGB324 sensitizes myofibroblasts to apoptosis. Finally, AXL inhibition with BGB324 blocks TGF-β1-induced fibrogenic gene and protein expression in human Intestinal organoids. Conclusions The AXL pathway is active in multiple models of Intestinal Fibrosis. In vitro experiments suggest that inhibiting AXL signaling could represent a novel approach to antifibrotic therapy for Intestinal Fibrosis such as in Crohn's disease.
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Quantitative assessment of Intestinal Fibrosis in vivo with spectroscopic and strain by endoscopic photoacoustic imaging
Biophotonics Congress: Biomedical Optics 2020 (Translational Microscopy OCT OTS BRAIN), 2020Co-Authors: Hao Lei, Laura A. Johnson, Yunhao Zhu, Kate Eaton, Jonathan M. Rubin, Xuedingwang, Peter D.r. HigginsAbstract:This study investigates on the molecular and mechanical markers of Intestinal Fibrosis in Crohn’s Disease using endoscopic photoacoustic imaging. The quantitative imaging results in vivo are validated by histology and microelastometry.
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Challenges in the Pathophysiology, Diagnosis and Management of Intestinal Fibrosis in Inflammatory Bowel Disease.
Gastroenterology, 2019Co-Authors: Geert R. D'haens, Peter D.r. Higgins, Florian Rieder, Gerhard Rogler, Brian G. Feagan, Julián Panés, Christian Maaser, Mark Löwenberg, Robbert Van Der Voort, Massimo PinzaniAbstract:Intestinal Fibrosis is a common complication of inflammatory bowel disease (IBD) that is usually the consequence of chronic inflammation. Although the currently available anti-inflammatory therapies have had little impact on Intestinal Fibrosis in Crohn's disease (CD), increased understanding of the pathophysiology and the development of therapies targeting fibrogenic pathways hold promise for the future. One of the critical challenges is how reduction or reversal of Intestinal Fibrosis should be defined and measured in the setting of clinical trials and drug approval. The International Organization for Inflammatory Bowel Disease (IOIBD) organized a workshop in Amsterdam, The Netherlands, on December 19th and 20th, 2018 in an attempt to review the current knowledge of the biological background, diagnosis, treatment of Intestinal Fibrosis and clinical trial endpoints. Basic and clinical scientists discussed the pathophysiology of Intestinal Fibrosis, the current status of biomarkers and imaging modalities in stenosing CD, and recent clinical studies in this area. Researchers from outside of the IBD field presented advances in the understanding of fibrotic processes in other organs, such as the skin, liver and lungs. Lastly, the design of clinical trials with antifibrotic therapy for IBD was discussed, with priority on patient populations, patient reported outcomes (PROs) and imaging. This report summarizes the key findings, discussions and conclusions of the workshop.
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Flagellin-mediated activation of IL-33-ST2 signaling by a pathobiont promotes Intestinal Fibrosis
Mucosal immunology, 2019Co-Authors: Jin Imai, Peter D.r. Higgins, Sho Kitamoto, Kohei Sugihara, Hiroko Nagao-kitamoto, Atsushi Hayashi, Tina L. Morhardt, Peter Kuffa, Nicolas Barnich, Nobuhiko KamadaAbstract:Intestinal Fibrosis is a severe complication in patients with Crohn's disease (CD). Unfortunately, the trigger leading to the development of Intestinal Fibrosis in the context of CD remains elusive. Here, we show that colonization by a CD-associated pathobiont adherent-invasive Escherichia coli (AIEC) promotes the development of Intestinal Fibrosis. Exogenously inoculated AIEC strain LF82 and commensal E. coli HS were gradually eradicated from the intestine in healthy mice. In Salmonella- or dextran sodium sulfate-induced colitis models, AIEC exploited inflammation and stably colonize the gut. Consequently, persistent colonization by AIEC LF82 led to substantial Fibrosis. In contrast, commensal E. coli HS was unable to derive a growth advantage from inflammation, thereby failing to colonize the inflamed intestine or promote Intestinal Fibrosis. AIEC colonization potentiated the expression of the IL-33 receptor ST2 in the Intestinal epithelium, which is crucial for the development of Intestinal Fibrosis. The induction of ST2 by AIEC LF82 was mediated by flagellin, as the ΔfliC mutant failed to induce ST2. These observations provide novel insights into pathobiont-driven Intestinal Fibrosis and can lead to the development of novel therapeutic approaches for the treatment of Intestinal Fibrosis in the context of CD that target AIEC and/or its downstream IL-33-ST2 signaling.
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Optimisation of Intestinal Fibrosis and Survival in the Mouse S. Typhimurium Model for Anti-fibrotic Drug Discovery and Preclinical Applications.
Journal of Crohn's & colitis, 2017Co-Authors: Laura A. Johnson, Eva S. Rodansky, David S. Moons, Scott D. Larsen, Richard R. Neubig, Peter D.r. HigginsAbstract:Background and aims Intestinal Fibrosis is a frequent complication in Crohn's disease [CD]. The mouse Salmonella typhimurium model, due to its simplicity, reproducibility, manipulability, and penetrance, is an established Fibrosis model for drug discovery and preclinical trials. However, the severity of Fibrosis and mortality are host- and bacterial strain-dependent, thus limiting the original model. We re-evaluated the S. typhimurium model to optimise Fibrosis and survival, using commercially available mouse strains. Methods Fibrotic and inflammatory markers were evaluated across S. typhimurium ΔaroA:C57bl/6 studies performed in our laboratory. A model optimisation study was performed using three commercially available mouse strains [CBA/J, DBA/J, and 129S1/SvImJ] infected with either SL1344 or ΔaroA S. typhimurium. Fibrotic penetrance was determined by histopathology, gene expression, and αSMA protein expression. Fibrosis severity, penetrance, and survival were analysed across subsequent CBA studies. Results Fibrosis severity and survival are both host- and bacterial strain-dependent. Marked tissue Fibrosis and 100% survival occurred in the CBA/J strain infected with SL1344. Subsequent experiments demonstrated that CBA/J mice develop extensive Intestinal Fibrosis, characterised by transmural tissue Fibrosis, a Th1/Th17 cytokine response, and induction of pro-fibrotic genes and extracellular matrix proteins. A meta-analysis of subsequent SL1344:CBA/J studies demonstrated that Intestinal Fibrosis is consistent and highly penetrant across histological, protein, and gene expression markers. As proof-of-concept, we tested the utility of the SL1344:CBA/J Fibrosis model to evaluate efficacy of CCG-203971, a novel anti-fibrotic drug. Conclusion The S. typhimurium SL1344:CBA/J model is an optimised model for the study of Intestinal Fibrosis.
Giovanni Latella - One of the best experts on this subject based on the ideXlab platform.
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Controversial Contribution of Th17/IL-17 Toward the Immune Response in Intestinal Fibrosis
Digestive Diseases and Sciences, 2020Co-Authors: Giovanni Latella, Angelo ViscidoAbstract:Intestinal Fibrosis is a common outcome of inflammatory bowel diseases (IBDs), becoming clinically apparent in 40% of patients with Crohn’s disease and 5% of those with ulcerative colitis. Effective pharmacological treatments aimed at controlling or reversing Fibrosis progression are unavailable. Fibrosis is characterized by an excessive local accumulation of extracellular matrix proteins (mainly collagen), as a result of their increased production by activated myofibroblasts and/or their reduced degradation by specific matrix metalloproteinases. Initiation and progression of Fibrosis are modulated by several pro- and anti-fibrogenic molecules. In recent years, the cytokine interleukin-17 (IL-17) has been integrated into the pathogenesis of Fibrosis, although its precise contribution to IBD, and especially to its related Intestinal Fibrosis, remains controversial. Several data suggest both a pro-inflammatory and pro-fibrotic action and a protective function of the Th17/IL-17 immune response. A recent study has demonstrated that the treatment with anti-IL-17 antibody significantly alleviated 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colorectal Fibrosis in mice by down-regulating the expression of collagen 3 and several pro-fibrogenic cytokines. Here, we describe and discuss the possible involvement of the Th17/IL-17 immune response in the initiation ad progression of Intestinal Fibrosis.
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controversial contribution of th17 il 17 toward the immune response in Intestinal Fibrosis
Digestive Diseases and Sciences, 2020Co-Authors: Giovanni Latella, Angelo ViscidoAbstract:Intestinal Fibrosis is a common outcome of inflammatory bowel diseases (IBDs), becoming clinically apparent in 40% of patients with Crohn's disease and 5% of those with ulcerative colitis. Effective pharmacological treatments aimed at controlling or reversing Fibrosis progression are unavailable. Fibrosis is characterized by an excessive local accumulation of extracellular matrix proteins (mainly collagen), as a result of their increased production by activated myofibroblasts and/or their reduced degradation by specific matrix metalloproteinases. Initiation and progression of Fibrosis are modulated by several pro- and anti-fibrogenic molecules. In recent years, the cytokine interleukin-17 (IL-17) has been integrated into the pathogenesis of Fibrosis, although its precise contribution to IBD, and especially to its related Intestinal Fibrosis, remains controversial. Several data suggest both a pro-inflammatory and pro-fibrotic action and a protective function of the Th17/IL-17 immune response. A recent study has demonstrated that the treatment with anti-IL-17 antibody significantly alleviated 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colorectal Fibrosis in mice by down-regulating the expression of collagen 3 and several pro-fibrogenic cytokines. Here, we describe and discuss the possible involvement of the Th17/IL-17 immune response in the initiation ad progression of Intestinal Fibrosis.
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Redox Imbalance in Intestinal Fibrosis: Beware of the TGFβ-1, ROS, and Nrf2 Connection.
Digestive diseases and sciences, 2017Co-Authors: Giovanni LatellaAbstract:Intestinal Fibrosis, a common complication of inflammatory bowel diseases, becomes clinically apparent in ~ 40% of patients with Crohn’s disease and ~ 5% of those with ulcerative colitis. Fibrosis, a consequence of local chronic inflammation, is characterized by excessive deposition of extracellular matrix (ECM) proteins by activated myofibroblasts, which are modulated by pro-fibrotic and anti-fibrotic factors. Fibrosis depends on the balance between production and degradation of ECM proteins. Although the transforming growth factor (TGF)-β1/Smad pathway is the major driving force of Fibrosis, several pro-fibrogenic and anti-fibrogenic endogenous factors appear to interact directly with this pathway such as reactive oxygen species (ROS) and nuclear factor-erythroid 2-related factor 2 (Nrf2), which are connected with TGF-β1 during Fibrosis development in several organs, including the intestine. Nrf2 is a ubiquitous master transcription factor that upregulates the expression of antioxidant enzymes and cytoprotective proteins mediated by antioxidant response elements (AREs). Here, I describe and discuss the links among TGF-β1, ROS, and Nrf2–AREs in the pathogenesis of Intestinal Fibrosis.
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Cellular and Molecular Mediators of Intestinal Fibrosis.
Journal of Crohn's & colitis, 2017Co-Authors: Ian C. Lawrance, Silvia Speca, Gerhard Rogler, Giorgos Bamias, Christine Breynaert, Jon Florholmen, Gianluca Pellino, Shimon Reif, Giovanni LatellaAbstract:Intestinal Fibrosis is a major complication of the inflammatory bowel diseases (IBD) and although inflammation is necessary for its development, it would appear that it plays a minor role in its progression as anti-inflammatory treatments in IBD do not prevent Fibrosis once it has started. The processes that regulate Fibrosis would thus appear to be distinct from those regulating inflammation and, therefore, a detailed understanding of these pathways is vital to the development of anti-fibrogenic strategies. There have been several recent reviews exploring what is known, and what remains unknown, about the development of Intestinal Fibrosis. This review is designed to add to this literature but with a focus on the cellular components that are involved in the development of fibrogenesis and the major molecular mediators that impact on these cells. The aim is to heighten the understanding of the factors involved in Intestinal fibrogenesis so that detailed research can be encouraged in order to advance the processes that could lead to effective treatments.
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Intestinal Fibrosis: ready to be reversed
Current opinion in gastroenterology, 2017Co-Authors: Giovanni Latella, Florian RiederAbstract:Purpose of reviewIntestinal Fibrosis is a common complication of several enteropathies, with inflammatory bowel disease (IBD) being the major cause. Intestinal Fibrosis affects both ulcerative colitis and Crohn's disease, and no specific antifibrotic therapy exists. This review highlights recent dev
Florian Rieder - One of the best experts on this subject based on the ideXlab platform.
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Noncoding RNAs as Promising Diagnostic Biomarkers and Therapeutic Targets in Intestinal Fibrosis of Crohn's Disease: The Path From Bench to Bedside.
Inflammatory bowel diseases, 2020Co-Authors: Long-yuan Zhou, Florian Rieder, Sinan Lin, Minhu Chen, Shenghong Zhang, Ren MaoAbstract:Fibrosis is a major pathway to organ injury and failure, accounting for more than one-third of deaths worldwide. Intestinal Fibrosis causes irreversible and serious clinical complications, such as strictures and obstruction, secondary to a complex pathogenesis. Under the stimulation of profibrotic soluble factors, excessive activation of mesenchymal cells causes extracellular matrix deposition via canonical transforming growth factor-β/Smads signaling or other pathways (eg, epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition) in Intestinal fibrogenesis. In recent studies, the importance of noncoding RNAs (ncRNAs) stands out in fibrotic diseases in that ncRNAs exhibit a remarkable variety of biological functions in modulating the aforementioned fibrogenic responses. In this review, we summarize the role of ncRNAs, including the emerging long ncRNAs and circular RNAs, in Intestinal fibrogenesis. Notably, the translational potential of ncRNAs as diagnostic biomarkers and therapeutic targets in the management of Intestinal Fibrosis is discussed based on clinical trials from fibrotic diseases in other organs. The main points of this review include the following: • Characteristics of ncRNAs and mechanisms of Intestinal fibrogenesis • Wide participation of ncRNAs (especially the emerging long ncRNAs and circular RNAs) in Intestinal Fibrosis, including transforming growth factor-β signaling, epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition, and extracellular matrix remodeling • Translational potential of ncRNAs in the diagnosis and treatment of Intestinal Fibrosis based on clinical trials from fibrotic diseases in other organs.
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Challenges in the Pathophysiology, Diagnosis and Management of Intestinal Fibrosis in Inflammatory Bowel Disease.
Gastroenterology, 2019Co-Authors: Geert R. D'haens, Peter D.r. Higgins, Florian Rieder, Gerhard Rogler, Brian G. Feagan, Julián Panés, Christian Maaser, Mark Löwenberg, Robbert Van Der Voort, Massimo PinzaniAbstract:Intestinal Fibrosis is a common complication of inflammatory bowel disease (IBD) that is usually the consequence of chronic inflammation. Although the currently available anti-inflammatory therapies have had little impact on Intestinal Fibrosis in Crohn's disease (CD), increased understanding of the pathophysiology and the development of therapies targeting fibrogenic pathways hold promise for the future. One of the critical challenges is how reduction or reversal of Intestinal Fibrosis should be defined and measured in the setting of clinical trials and drug approval. The International Organization for Inflammatory Bowel Disease (IOIBD) organized a workshop in Amsterdam, The Netherlands, on December 19th and 20th, 2018 in an attempt to review the current knowledge of the biological background, diagnosis, treatment of Intestinal Fibrosis and clinical trial endpoints. Basic and clinical scientists discussed the pathophysiology of Intestinal Fibrosis, the current status of biomarkers and imaging modalities in stenosing CD, and recent clinical studies in this area. Researchers from outside of the IBD field presented advances in the understanding of fibrotic processes in other organs, such as the skin, liver and lungs. Lastly, the design of clinical trials with antifibrotic therapy for IBD was discussed, with priority on patient populations, patient reported outcomes (PROs) and imaging. This report summarizes the key findings, discussions and conclusions of the workshop.
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Persistent Salmonella enterica Serovar Typhimurium Infection Induces Protease Expression During Intestinal Fibrosis.
Inflammatory bowel diseases, 2019Co-Authors: Katrin Ehrhardt, Florian Rieder, Ilyssa Gordon, Natalie Steck, Reinhild Kappelhoff, Stephanie Stein, Erin C. Boyle, Peter Braubach, Christopher M. Overall, B. Brett FinlayAbstract:Background Intestinal Fibrosis is a common and serious complication of Crohn's disease characterized by the accumulation of fibroblasts, deposition of extracellular matrix, and formation of scar tissue. Although many factors including cytokines and proteases contribute to the development of Intestinal Fibrosis, the initiating mechanisms and the complex interplay between these factors remain unclear. Methods Chronic infection of mice with Salmonella enterica serovar Typhimurium was used to induce Intestinal Fibrosis. A murine protease-specific CLIP-CHIP microarray analysis was employed to assess regulation of proteases and protease inhibitors. To confirm up- or downregulation during Fibrosis, we performed quantitative real-time polymerase chain reaction (PCR) and immunohistochemical stainings in mouse tissue and tissue from patients with inflammatory bowel disease. In vitro infections were used to demonstrate a direct effect of bacterial infection in the regulation of proteases. Results Mice develop severe and persistent Intestinal Fibrosis upon chronic infection with Salmonella enterica serovar Typhimurium, mimicking the pathology of human disease. Microarray analyses revealed 56 up- and 40 downregulated proteases and protease inhibitors in fibrotic cecal tissue. Various matrix metalloproteases, serine proteases, cysteine proteases, and protease inhibitors were regulated in the fibrotic tissue, 22 of which were confirmed by quantitative real-time PCR. Proteases demonstrated site-specific staining patterns in Intestinal fibrotic tissue from mice and in tissue from human inflammatory bowel disease patients. Finally, we show in vitro that Salmonella infection directly induces protease expression in macrophages and epithelial cells but not in fibroblasts. Conclusions In summary, we show that chronic Salmonella infection regulates proteases and protease inhibitors during tissue Fibrosis in vivo and in vitro, and therefore this model is well suited to investigating the role of proteases in Intestinal Fibrosis.
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Pathogenesis of Intestinal Fibrosis in Inflammatory Bowel Disease and Perspectives for Therapeutic Implication.
Digestive diseases (Basel Switzerland), 2017Co-Authors: Dominik Bettenworth, Florian RiederAbstract:Background: Intestinal Fibrosis with stricture formation is a common feature of inflammatory bowel disease (IBD) and leads to a significantly impaired quality of life in affected patients, Intestinal obstruction as well as to the need for surgical intervention. This constitutes a major treatment challenge. Key Messages: Fibrosis results from the response of gut tissue to the insult inflicted by chronic inflammation. Similarly to what occurs in other organs, the underlying fibrogenic mechanisms are complex and dynamic, involving multiple cell types, interrelated cellular events, and a large number of soluble factors. Owing to a breakdown of the epithelial barrier in IBD, luminal bacterial products leak into the interstitium and induce an innate immune response mediated by the activation of both immune and non-immune cells. Other environmental factors as well as chronic inflammation will certainly impact the quality and quantity of Intestinal Fibrosis. Finally, the composition of the Intestinal extracellular matrix is dramatically altered in chronic gut inflammation and actively promotes Fibrosis through its mechanical properties. The conventional view that Intestinal Fibrosis is an inevitable and irreversible process is gradually changing in light of an improved understanding of the cellular and molecular mechanisms that underline its pathogenesis. In addition, clinical observations in patients who undergo strictureplasty have shown that stricture formation is reversible. Conclusions: Identification of the unique mechanisms of Intestinal fibrogenesis should create a practical framework to target and block specific fibrogenic pathways, estimate the risk of fibrotic complications, permit the detection of early fibrotic changes and, eventually, allow the development of treatment methods customized to each patient's type and degree of Intestinal Fibrosis.
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Intestinal Fibrosis: ready to be reversed
Current opinion in gastroenterology, 2017Co-Authors: Giovanni Latella, Florian RiederAbstract:Purpose of reviewIntestinal Fibrosis is a common complication of several enteropathies, with inflammatory bowel disease (IBD) being the major cause. Intestinal Fibrosis affects both ulcerative colitis and Crohn's disease, and no specific antifibrotic therapy exists. This review highlights recent dev
Ian C. Lawrance - One of the best experts on this subject based on the ideXlab platform.
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Cellular and Molecular Mediators of Intestinal Fibrosis.
Journal of Crohn's & colitis, 2017Co-Authors: Ian C. Lawrance, Silvia Speca, Gerhard Rogler, Giorgos Bamias, Christine Breynaert, Jon Florholmen, Gianluca Pellino, Shimon Reif, Giovanni LatellaAbstract:Intestinal Fibrosis is a major complication of the inflammatory bowel diseases (IBD) and although inflammation is necessary for its development, it would appear that it plays a minor role in its progression as anti-inflammatory treatments in IBD do not prevent Fibrosis once it has started. The processes that regulate Fibrosis would thus appear to be distinct from those regulating inflammation and, therefore, a detailed understanding of these pathways is vital to the development of anti-fibrogenic strategies. There have been several recent reviews exploring what is known, and what remains unknown, about the development of Intestinal Fibrosis. This review is designed to add to this literature but with a focus on the cellular components that are involved in the development of fibrogenesis and the major molecular mediators that impact on these cells. The aim is to heighten the understanding of the factors involved in Intestinal fibrogenesis so that detailed research can be encouraged in order to advance the processes that could lead to effective treatments.
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Prostaglandin E2 and Polyenylphosphatidylcholine Protect Against Intestinal Fibrosis and Regulate Myofibroblast Function
Digestive diseases and sciences, 2015Co-Authors: Angela Baird, Frances Lloyd, Ian C. LawranceAbstract:Background Intestinal Fibrosis is a serious and often recurrent complication of inflammatory bowel disease despite surgical intervention. The anti-fibrotic potential of prostaglandin E2 (PGE2) and polyenylphosphatidylcholine (PC) was investigated using the murine model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced chronic Intestinal inflammation and Fibrosis, and murine and human Intestinal myofibroblasts.
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Mechanisms of initiation and progression of Intestinal Fibrosis in IBD
Scandinavian journal of gastroenterology, 2014Co-Authors: Giovanni Latella, Florian Rieder, Jacopo Di Gregorio, Vincenzo Flati, Ian C. LawranceAbstract: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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Results of the 4th scientific workshop of the ECCO (I): Pathophysiology of Intestinal Fibrosis in IBD
Journal of Crohn's & colitis, 2014Co-Authors: Giovanni Latella, Silvia Speca, Gerhard Rogler, Giorgos Bamias, Christine Breynaert, Jon Florholmen, Gianluca Pellino, Shimon Reif, Ian C. LawranceAbstract:The fourth scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of Intestinal Fibrosis in the disease course of inflammatory bowel disease (IBD). The objective was to better understand the pathophysiological mechanisms of Intestinal Fibrosis, to identify useful markers and imaging modalities of Fibrosis in order to assess its presence and progression, and, finally, to point out possible approaches for the prevention and the treatment of Fibrosis. The results of this workshop are presented in three separate manuscripts. This first section describes the most important mechanisms that contribute to the initiation and progression of Intestinal Fibrosis in IBD including the cellular and molecular mediators, the extracellular matrix molecules and matrix metalloproteinases/tissue inhibitors of metalloproteinases-system, the microbiota products, the role of fat, genetic and epigenetic factors, as well as the currently available experimental models. Furthermore, it identifies unanswered questions in the field of Intestinal Fibrosis and provides a framework for future research.
Gerhard Rogler - One of the best experts on this subject based on the ideXlab platform.
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Challenges in the Pathophysiology, Diagnosis and Management of Intestinal Fibrosis in Inflammatory Bowel Disease.
Gastroenterology, 2019Co-Authors: Geert R. D'haens, Peter D.r. Higgins, Florian Rieder, Gerhard Rogler, Brian G. Feagan, Julián Panés, Christian Maaser, Mark Löwenberg, Robbert Van Der Voort, Massimo PinzaniAbstract:Intestinal Fibrosis is a common complication of inflammatory bowel disease (IBD) that is usually the consequence of chronic inflammation. Although the currently available anti-inflammatory therapies have had little impact on Intestinal Fibrosis in Crohn's disease (CD), increased understanding of the pathophysiology and the development of therapies targeting fibrogenic pathways hold promise for the future. One of the critical challenges is how reduction or reversal of Intestinal Fibrosis should be defined and measured in the setting of clinical trials and drug approval. The International Organization for Inflammatory Bowel Disease (IOIBD) organized a workshop in Amsterdam, The Netherlands, on December 19th and 20th, 2018 in an attempt to review the current knowledge of the biological background, diagnosis, treatment of Intestinal Fibrosis and clinical trial endpoints. Basic and clinical scientists discussed the pathophysiology of Intestinal Fibrosis, the current status of biomarkers and imaging modalities in stenosing CD, and recent clinical studies in this area. Researchers from outside of the IBD field presented advances in the understanding of fibrotic processes in other organs, such as the skin, liver and lungs. Lastly, the design of clinical trials with antifibrotic therapy for IBD was discussed, with priority on patient populations, patient reported outcomes (PROs) and imaging. This report summarizes the key findings, discussions and conclusions of the workshop.
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Myeloid differentiation primary response gene (MyD) 88 signalling is not essential for Intestinal Fibrosis development.
Scientific reports, 2017Co-Authors: Christian Lutz, Bruce Weder, Gerhard Rogler, Anouk Hünerwadel, Stefania Fagagnini, Brian M. Lang, Niko Beerenwinkel, Jean-benoit Rossel, Benjamin Misselwitz, Martin HausmannAbstract:Dysregulation of the immune response to microbiota is associated with inflammatory bowel disease (IBD), which can trigger Intestinal Fibrosis. MyD88 is a key component of microbiota signalling but its influence on Intestinal Fibrosis has not been clarified. Small bowel resections from donor-mice were transplanted subcutaneously into the neck of recipients C57BL/6 B6-MyD88tm1 Aki (MyD88-/-) and C57BL/6-Tg(UBC-green fluorescence protein (GFP))30Scha/J (GFP-Tg). Grafts were explanted up to 21 days after transplantation. Collagen layer thickness was determined using Sirius Red stained slides. In the mouse model of Fibrosis collagen deposition and transforming growth factor-beta 1 (TGF-β1) expression was equal in MyD88+/+ and MyD88-/-, indicating that MyD88 was not essential for fibrogenesis. Matrix metalloproteinase (Mmp)9 expression was significantly decreased in grafts transplanted into MyD88-/- recipients compared to MyD88+/+ recipients (0.2 ± 0.1 vs. 153.0 ± 23.1, respectively, p
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Cellular and Molecular Mediators of Intestinal Fibrosis.
Journal of Crohn's & colitis, 2017Co-Authors: Ian C. Lawrance, Silvia Speca, Gerhard Rogler, Giorgos Bamias, Christine Breynaert, Jon Florholmen, Gianluca Pellino, Shimon Reif, Giovanni LatellaAbstract:Intestinal Fibrosis is a major complication of the inflammatory bowel diseases (IBD) and although inflammation is necessary for its development, it would appear that it plays a minor role in its progression as anti-inflammatory treatments in IBD do not prevent Fibrosis once it has started. The processes that regulate Fibrosis would thus appear to be distinct from those regulating inflammation and, therefore, a detailed understanding of these pathways is vital to the development of anti-fibrogenic strategies. There have been several recent reviews exploring what is known, and what remains unknown, about the development of Intestinal Fibrosis. This review is designed to add to this literature but with a focus on the cellular components that are involved in the development of fibrogenesis and the major molecular mediators that impact on these cells. The aim is to heighten the understanding of the factors involved in Intestinal fibrogenesis so that detailed research can be encouraged in order to advance the processes that could lead to effective treatments.
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Hallmarks of epithelial to mesenchymal transition are detectable in Crohn’s disease associated Intestinal Fibrosis
Clinical and translational medicine, 2015Co-Authors: Michael Scharl, Nicole Huber, Silvia Lang, Alois Fürst, Ekkehard C. Jehle, Gerhard RoglerAbstract:Background Intestinal Fibrosis and subsequent stricture formation represent frequent complications of Crohn’s disease (CD). In many organs, Fibrosis develops as a result of epithelial to mesenchymal transition (EMT). Recent studies suggested that EMT could be involved in Intestinal Fibrosis as a result of chronic inflammation. Here, we investigated whether EMT might be involved in stricture formation in CD patients.
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hallmarks of epithelial to mesenchymal transition are detectable in crohn s disease associated Intestinal Fibrosis
Clinical and translational medicine, 2015Co-Authors: Michael Scharl, Nicole Huber, Silvia Lang, Alois Fürst, Ekkehard C. Jehle, Gerhard RoglerAbstract:Background Intestinal Fibrosis and subsequent stricture formation represent frequent complications of Crohn’s disease (CD). In many organs, Fibrosis develops as a result of epithelial to mesenchymal transition (EMT). Recent studies suggested that EMT could be involved in Intestinal Fibrosis as a result of chronic inflammation. Here, we investigated whether EMT might be involved in stricture formation in CD patients.
