The Effect of a Novel Serine Protease Inhibitor on Inflammation and Intestinal Permeability in a Murine Colitis Transfer Model
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...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-06-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.682065/full |
| _version_ | 1830199053160284160 |
|---|---|
| author | Hanne Van Spaendonk Hanne Van Spaendonk Hannah Ceuleers Hannah Ceuleers Annemieke Smet Annemieke Smet Maya Berg Jurgen Joossens Pieter Van der Veken Pieter Van der Veken Sven M. Francque Sven M. Francque Sven M. Francque Anne-Marie Lambeir Anne-Marie Lambeir Joris G. De Man Joris G. De Man Ingrid De Meester Ingrid De Meester Koen Augustyns Koen Augustyns Benedicte Y. De Winter Benedicte Y. De Winter Benedicte Y. De Winter |
| author_facet | Hanne Van Spaendonk Hanne Van Spaendonk Hannah Ceuleers Hannah Ceuleers Annemieke Smet Annemieke Smet Maya Berg Jurgen Joossens Pieter Van der Veken Pieter Van der Veken Sven M. Francque Sven M. Francque Sven M. Francque Anne-Marie Lambeir Anne-Marie Lambeir Joris G. De Man Joris G. De Man Ingrid De Meester Ingrid De Meester Koen Augustyns Koen Augustyns Benedicte Y. De Winter Benedicte Y. De Winter Benedicte Y. De Winter |
| author_sort | Hanne Van Spaendonk |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T02:06:35Z |
| format | Article |
| id | doaj.art-21b5fe8dc7624ef18c29d312443ee481 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-18T02:06:35Z |
| publishDate | 2021-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-21b5fe8dc7624ef18c29d312443ee4812022-12-21T21:24:35ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-06-011210.3389/fphar.2021.682065682065The Effect of a Novel Serine Protease Inhibitor on Inflammation and Intestinal Permeability in a Murine Colitis Transfer ModelHanne Van Spaendonk0Hanne Van Spaendonk1Hannah Ceuleers2Hannah Ceuleers3Annemieke Smet4Annemieke Smet5Maya Berg6Jurgen Joossens7Pieter Van der Veken8Pieter Van der Veken9Sven M. Francque10Sven M. Francque11Sven M. Francque12Anne-Marie Lambeir13Anne-Marie Lambeir14Joris G. De Man15Joris G. De Man16Ingrid De Meester17Ingrid De Meester18Koen Augustyns19Koen Augustyns20Benedicte Y. De Winter21Benedicte Y. De Winter22Benedicte Y. De Winter23Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, BelgiumInfla-Med, Centre of Excellence, University of Antwerp, Antwerp, BelgiumLaboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, BelgiumInfla-Med, Centre of Excellence, University of Antwerp, Antwerp, BelgiumLaboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, BelgiumInfla-Med, Centre of Excellence, University of Antwerp, Antwerp, BelgiumInfla-Med, Centre of Excellence, University of Antwerp, Antwerp, BelgiumLaboratory of Medicinal Chemistry, University of Antwerp, Antwerp, BelgiumInfla-Med, Centre of Excellence, University of Antwerp, Antwerp, BelgiumLaboratory of Medicinal Chemistry, University of Antwerp, Antwerp, BelgiumLaboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, BelgiumInfla-Med, Centre of Excellence, University of Antwerp, Antwerp, BelgiumDivision of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, BelgiumInfla-Med, Centre of Excellence, University of Antwerp, Antwerp, BelgiumLaboratory of Medical Biochemistry, University of Antwerp, Antwerp, BelgiumLaboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, BelgiumInfla-Med, Centre of Excellence, University of Antwerp, Antwerp, BelgiumInfla-Med, Centre of Excellence, University of Antwerp, Antwerp, BelgiumLaboratory of Medical Biochemistry, University of Antwerp, Antwerp, BelgiumInfla-Med, Centre of Excellence, University of Antwerp, Antwerp, BelgiumLaboratory of Medicinal Chemistry, University of Antwerp, Antwerp, BelgiumLaboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, BelgiumInfla-Med, Centre of Excellence, University of Antwerp, Antwerp, BelgiumDivision of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, BelgiumBackground: 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.https://www.frontiersin.org/articles/10.3389/fphar.2021.682065/fullT cell transfer colitis mouse modelserine protease inhibitorintestinal barrierT cellsprotease-activated receptors |
| spellingShingle | Hanne Van Spaendonk Hanne Van Spaendonk Hannah Ceuleers Hannah Ceuleers Annemieke Smet Annemieke Smet Maya Berg Jurgen Joossens Pieter Van der Veken Pieter Van der Veken Sven M. Francque Sven M. Francque Sven M. Francque Anne-Marie Lambeir Anne-Marie Lambeir Joris G. De Man Joris G. De Man Ingrid De Meester Ingrid De Meester Koen Augustyns Koen Augustyns Benedicte Y. De Winter Benedicte Y. De Winter Benedicte Y. De Winter The Effect of a Novel Serine Protease Inhibitor on Inflammation and Intestinal Permeability in a Murine Colitis Transfer Model Frontiers in Pharmacology T cell transfer colitis mouse model serine protease inhibitor intestinal barrier T cells protease-activated receptors |
| title | The Effect of a Novel Serine Protease Inhibitor on Inflammation and Intestinal Permeability in a Murine Colitis Transfer Model |
| title_full | The Effect of a Novel Serine Protease Inhibitor on Inflammation and Intestinal Permeability in a Murine Colitis Transfer Model |
| title_fullStr | The Effect of a Novel Serine Protease Inhibitor on Inflammation and Intestinal Permeability in a Murine Colitis Transfer Model |
| title_full_unstemmed | The Effect of a Novel Serine Protease Inhibitor on Inflammation and Intestinal Permeability in a Murine Colitis Transfer Model |
| title_short | The Effect of a Novel Serine Protease Inhibitor on Inflammation and Intestinal Permeability in a Murine Colitis Transfer Model |
| title_sort | effect of a novel serine protease inhibitor on inflammation and intestinal permeability in a murine colitis transfer model |
| topic | T cell transfer colitis mouse model serine protease inhibitor intestinal barrier T cells protease-activated receptors |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.682065/full |
| work_keys_str_mv | AT hannevanspaendonk theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT hannevanspaendonk theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT hannahceuleers theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT hannahceuleers theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT annemiekesmet theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT annemiekesmet theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT mayaberg theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT jurgenjoossens theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT pietervanderveken theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT pietervanderveken theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT svenmfrancque theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT svenmfrancque theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT svenmfrancque theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT annemarielambeir theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT annemarielambeir theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT jorisgdeman theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT jorisgdeman theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT ingriddemeester theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT ingriddemeester theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT koenaugustyns theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT koenaugustyns theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT benedicteydewinter theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT benedicteydewinter theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT benedicteydewinter theeffectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT hannevanspaendonk effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT hannevanspaendonk effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT hannahceuleers effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT hannahceuleers effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT annemiekesmet effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT annemiekesmet effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT mayaberg effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT jurgenjoossens effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT pietervanderveken effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT pietervanderveken effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT svenmfrancque effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT svenmfrancque effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT svenmfrancque effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT annemarielambeir effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT annemarielambeir effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT jorisgdeman effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT jorisgdeman effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT ingriddemeester effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT ingriddemeester effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT koenaugustyns effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT koenaugustyns effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT benedicteydewinter effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT benedicteydewinter effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel AT benedicteydewinter effectofanovelserineproteaseinhibitoroninflammationandintestinalpermeabilityinamurinecolitistransfermodel |