|
Title
|
|
|
|
The effect of a novel serine protease inhibitor on inflammation and intestinal permeability in a murine colitis transfer model
| |
|
Author
|
|
|
|
| |
|
Abstract
|
|
|
|
| Background: A protease/antiprotease disbalance is observed in inflammatory bowel diseases (IBD). We therefore studied the effect of the novel serine protease inhibitor UAMC-00050 on intestinal inflammation and permeability in a chronic colitis T cell transfer mouse model to get further insight into the regulation of T cell-mediated immunopathology. Methods: Colitis was induced in severe combined immunodeficient (SCID) mice, by the adoptive transfer of CD4+CD25−CD62L+ T cells. Animals were treated intraperitoneally (i.p.) 2x/day with vehicle or UAMC-00050 (5 mg/kg) from week 2 onwards. Colonic inflammation was assessed by clinical parameters, colonoscopy, macroscopy, microscopy, myeloperoxidase activity and cytokine expression levels. At week 4, 4 kDa FITC-dextran intestinal permeability was evaluated and T helper transcription factors, protease-activated receptors and junctional proteins were quantified by RT-qPCR. Results: Adoptive transfer of CD4+CD25−CD62L+ T cells resulted in colonic inflammation and an altered intestinal permeability. The serine protease inhibitor UAMC-00050 ameliorated both the inflammatory parameters and the intestinal barrier function. Furthermore, a decrease in colonic mRNA expression of Tbet and PAR4 was observed in colitis mice after UAMC-00050 treatment. Conclusion: The beneficial effect of UAMC-00050 on inflammation was apparent via a reduction of Tbet, IFN-γ, TNF-α, IL-1β and IL-6. Based on these results, we hypothesize a pivotal effect of serine protease inhibition on the Th1 inflammatory profile potentially mediated via PAR4. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Frontiers in pharmacology. - [Lausanne, 2010, currens
| |
|
Publication
|
|
|
|
[Lausanne
:
Frontiers Media]
,
2021
| |
|
ISSN
|
|
|
|
1663-9812
| |
|
DOI
|
|
|
|
10.3389/FPHAR.2021.682065
| |
|
Volume/pages
|
|
|
|
12
(2021)
, p. 1-13
| |
|
Article Reference
|
|
|
|
682065
| |
|
ISI
|
|
|
|
000670587800001
| |
|
Pubmed ID
|
|
|
|
34248633
| |
|
Medium
|
|
|
|
E-only publicatie
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|
Full text (open access)
|
|
|
|
| |
|