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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
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Abstract
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ePub - 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. -
Citations
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- Novel Transcriptomic Signatures in Fibrostenotic Crohn’s Disease: Dysregulated Pathways, Promising Biomarkers, and Putative Therapeutic Targets
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