Newly developed serine protease inhibitors decrease visceral hypersensitivity in a post‐inflammatory rat model for irritable bowel syndrome
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Background and Purpose: Serine proteases have been re suggested as important mediators of visceral pain. We investigated their effect by using newly developed serine protease inhibitors with a well‐characterized inhibitory profile in a rat model of post‐inflammatory irritable bowel syndrome (IBS). Experimental Approach: Colitis was induced in rats receiving intrarectal trinitrobenzenesulphonic acid; controls received 0.9% NaCl. Colonoscopies were performed on day 3, to confirm colitis, and later until mucosal healing. Visceral hypersensitivity was quantified by visceromotor responses (VMRs) to colorectal distension, 30 min after i.p. injection of the serine protease inhibitors nafamostat, UAMC‐00050 or UAMC‐01162. Serine proteases, protease‐activated receptors (PARs) and TRP channels were quantified by qPCR and immunohistochemistry. Proteolytic activity was characterized using fluorogenic substrates. Key Results: VMR was significantly elevated in post‐colitis rats. Nafamostat normalized VMRs at the lowest dose tested. UAMC‐00050 and UAMC‐01162 significantly decreased VMR dose‐dependently. Expression of mRNA for tryptase‐αβ‐1and PAR4, and tryptase immunoreactivity was significantly increased in the colon of post‐colitis animals. Trypsin‐like activity was also significantly increased in the colon but not in the faeces. PAR2 and TRPA1 immunoreactivity co‐localized with CGRP‐positive nerve fibres in control and post‐colitis animals. Conclusions and Implications: Increased expression of serine proteases and activity together with increased expression of downstream molecules at the colonic and DRG level and in CGRP‐positive sensory nerve fibres imply a role for serine proteases in post‐inflammatory visceral hypersensitivity. Our results support further investigation of serine protease inhibitors as an interesting treatment strategy for IBS‐related visceral pain.
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Nafamostat, an inhibitor of serine proteases, reduced visceral hyperalgesia in a rodent model of post-inflammatory irritable bowel syndrome.
“In agreement with a role for enhanced protease activity in IBS, nafamostat, an inhibitor of serine proteases, reduced visceral hyperalgesia in a rodent model of post-inflammatory IBS.31”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [31]
Elafin, a Lactobacillus-derived inhibitor of serine proteases, reduces the severity of colitis in mice exposed to dextran sulfate sodium or trinitro benzene sulphonic acid.
“Elafin, a Lactobacillus-derived inhibitor of serine proteases reduced the severity of colitis in mice exposed to dextran sulfate sodium (DSS) or trinitro benzene sulphonic acid.27,30,31”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [31]
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- Authors
- Ceuleers, H., Hanning, N., Heirbaut, J., Van Remoortel, S., Joossens, J., Van Der Veken, P., Francque, S. M., De bruyn, M., Lambeir, A., De Man, J. G., Timmermans, J., Augustyns, K., De Meester, I., & De Winter, B. Y.
- Affiliations
- University of Antwerp (BE)
- Laboratory of Cell Biology and Histology University of Antwerp Antwerp Belgium
- Laboratory of Medicinal Chemistry University of Antwerp Antwerp Belgium
- Antwerp University Hospital (BE)
- Laboratory of Medical Biochemistry University of Antwerp Antwerp Belgium
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology University of Antwerp Antwerp Belgium
- ORCID
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2018-07-23
- Volume
- 175
- Issue
- 17
- Pages
- 3516-3533
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC6086981
- OpenAlex
- W2809374505
- Cited by
- 49
- References
- 57
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 5 · 2023: 8 · 2022: 8 · 2021: 9 · 2020: 3 · 2019: 4
- FWCI
- 3.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fonds Wetenschappelijk Onderzoek (G034113N)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Keywords
- serine protease inhibitors, irritable bowel syndrome, visceral hypersensitivity, visceral pain, nafamostat, protease-activated receptors, PAR4, tryptase, TRPA1, calcitonin gene-related peptide, sensory nerve fibers, visceromotor response, trypsin-like activity
- MeSH terms
- Animals, Disease Models, Animal, Male, Serine Proteinase Inhibitors, Rats, Sprague-Dawley, Irritable Bowel Syndrome, Rats, Visceral Pain
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