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

Research output: Contribution to journalArticle

Abstract

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. (Intest Res 2020;18:219-228).

Original languageEnglish
Article number0037
Pages (from-to)219-228
Number of pages10
JournalIntestinal Research
Volume18
Issue number2
DOIs
Publication statusPublished - 2020

Keywords

  • 2,4,6-trinitrobenzene sulfonic acid
  • Crohn disease
  • Intestinal fibrosis
  • Matrix metalloproteinase 9
  • Plasminogen activator inhibitor-1

ASJC Scopus subject areas

  • Gastroenterology

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    Imai, J., Yahata, T., Ichikawa, H., Ibrahim, A. A., Yazawa, M., Sumiyoshi, H., Inagaki, Y., Matsushima, M., Suzuki, T., Mine, T., Ando, K., Miyata, T., & Hozumi, K. (2020). Inhibition of plasminogen activator inhibitor-1 attenuates against intestinal fibrosis in mice. Intestinal Research, 18(2), 219-228. [0037]. https://doi.org/10.5217/IR.2019.00037