Newly developed serine protease inhibitors decrease visceral hypersensitivity in a post-inflammatory rat model for irritable bowel syndrome
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-alpha beta-1 and 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.
Source (journal)
British journal of pharmacology. - London
London : 2018
175 :17 (2018) , p. 3516-3533
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Project info
The role of afferent neurons and their modulation in the pathogenesis of postinflammatory gastrointestinal motility and sensitivity disturbances.
TRP channel sensitization as target for treatment of hypersensitivity (TRP-sensation).
The role of mucosal mediators and their effect on neuronal afferent signalling and intestinal permeability during postinflammatory visceral hypersensitivity: a translational study.
INFLA-MED - Fundamental research in the pathophysiological processes of inflammatory diseases.
Therapeutic modulation of the gastrointestinal permeability-inflammation-pain axis.
Publication type
Publications with a UAntwerp address
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Web of Science
Creation 07.09.2018
Last edited 09.10.2023
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