AI Article Synopsis

  • Intestinal fibrosis is a significant issue in Crohn's disease, primarily driven by the protein transforming growth factor-β (TGF-β), which promotes collagen and plasminogen activator inhibitor-1 (PAI-1) production, contributing to ECM buildup.
  • The study involved inducing chronic intestinal inflammation in mice and administering TM5275, a PAI-1 inhibitor, which showed promise in reducing collagen accumulation and promoting collagen degradation.
  • The findings suggest that targeting PAI-1 could offer a new treatment strategy for managing intestinal fibrosis in Crohn's disease patients.

Article Abstract

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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206341PMC
http://dx.doi.org/10.5217/ir.2019.00037DOI Listing

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