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KMID : 0988920200180020219
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Intestinal Research
2020 Volume.18 No. 2 p.219 ~ p.228
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Inhibition of plasminogen activator inhibitor-1 attenuates against intestinal fibrosis in mice
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Imai Jin
Yahata Takashi
Ibrahim Abd Aziz
Yazawa Masaki
Sumiyoshi Hideaki
Inagaki Yutaka
Matsushima Masashi
Suzuki Takayoshi
Mine Tetsuya
Ando Kiyoshi
Miyata Toshio
Hozumi Katsuto
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Abstract
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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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KEYWORD
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Plasminogen activator inhibitor-1, Matrix metalloproteinase 9, Intestinal fibrosis, Crohn disease, 2,4,6-Trinitrobenzene sulfonic acid
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