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IBD
Animal models of inflammatory bowel disease: novel experiments for revealing pathogenesis of colitis, fibrosis, and colitis-associated colon cancer
Chan Hyung Lee, Seong-Joon Koh, Zaher A Radi, Aida Habtezion
Intest Res 2023;21(3):295-305.   Published online May 31, 2023
DOI: https://doi.org/10.5217/ir.2023.00029
AbstractAbstract PDFPubReaderePub
Inflammatory bowel disease (IBD), comprising Crohn’s disease and ulcerative colitis, is a lifelong disease that manifests with chronic intestinal inflammation, sequential fibrosis, and an increased risk of colitis-associated colon cancer (CAC). The combined effects of genetic, immunological, environmental, and microbial factors render it difficult to determine the specific mechanism underlying the induction and perpetuation of IBD. Various animal models of IBD have contributed enormously to the understanding of IBD pathogenesis in terms of genomics, transcriptomics, proteomics, microbiome, and drug development of novel therapeutics. Although comprehensive research on IBD has been enabled by advanced technologies, such as genetically engineered models, there is a great need to develop relevant in vivo models of colitis and fibrosis. Here, we review 4 categories of animal models of acute and chronic intestinal inflammation, fibrosis, and CAC: chemically induced, genetically engineered, T cell transfer, and spontaneous gene mutation models.

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Inflammatory bowel diseases
Fibrostenotic strictures in Crohn’s disease
Jun Hwan Yoo, Stefan Holubar, Florian Rieder
Intest Res 2020;18(4):379-401.   Published online April 10, 2020
DOI: https://doi.org/10.5217/ir.2019.09148
AbstractAbstract PDFPubReaderePub
The use of biologic agents including anti-tumor necrosis factor monoclonal antibodies followed by anti-integrins and anti-interleukins has drastically changed the treatment paradigm of Crohn’s disease (CD) by improving clinical symptoms and mucosal healing. However, up to 70% of CD patients still eventually undergo surgery mainly due to fibrostenotic strictures. There are no specific anti-fibrotic drugs yet. This review comprehensively addresses the mechanism, prediction, diagnosis and treatment of the fibrostenotic strictures in CD. We also introduce promising anti-fibrotic agents which may be available in the near future and summarize challenges in developing novel therapies to treat fibrostenotic strictures in CD.

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Original Article
Inflammatory bowel diseases
Inhibition of plasminogen activator inhibitor-1 attenuates against intestinal fibrosis in mice
Jin Imai, Takashi Yahata, Hitoshi Ichikawa, Abd Aziz Ibrahim, Masaki Yazawa, Hideaki Sumiyoshi, Yutaka Inagaki, Masashi Matsushima, Takayoshi Suzuki, Tetsuya Mine, Kiyoshi Ando, Toshio Miyata, Katsuto Hozumi
Intest Res 2020;18(2):219-228.   Published online February 17, 2020
DOI: https://doi.org/10.5217/ir.2019.00037
AbstractAbstract PDFPubReaderePub
Background/Aims
Intestinal fibrosis is a major complication of Crohn’s disease (CD). The profibrotic protein transforming growth factor-β (TGF-β) has been considered to be critical for the induction of the fibrotic program. TGF-β has the ability to induce not only the expression of extracellular matrix (ECM) including collagen, but also the production of plasminogen activator inhibitor-1 (PAI-1) that prevents enzymatic degradation of the ECM during the onset of fibrotic diseases. However, the significance of PAI-1 in the developing intestinal fibrosis has not been fully understood. In the present study, we examined the actual expression of PAI-1 in fibrotic legion of intestinal inflammation and its correlation with the abnormal ECM deposition.
Methods
Chronic intestinal inflammation was induced in BALB/c mice using 8 repeated intrarectal injections of 2,4,6-trinitrobenzene sulfonic acid (TNBS). TM5275, a PAI-1 inhibitor, was orally administered as a carboxymethyl cellulose suspension each day for 2 weeks after the sixth TNBS injection.
Results
Using a publicly available dataset (accession number, GSE75214) and TNBS-treated mice, we observed increases in PAI-1 transcripts at active fibrotic lesions in both patients with CD and mice with chronic intestinal inflammation. Oral administration of TM5275 immediately after the onset of intestinal fibrosis upregulated MMP-9 (matrix metalloproteinase 9) and decreased collagen accumulation, resulting in attenuation of the fibrogenesis in TNBS-treated mice.
Conclusions
PAI-1-mediated fibrinolytic system facilitates collagen degradation suppression. Hence, PAI-1 inhibitor could be applied as an anti-fibrotic drug in CD treatment.

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