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Newly developed serine protease inhibitors decrease visceral hypersensitivity in a post‐inflammatory rat model for irritable bowel syndrome
Author(s) -
Ceuleers Hannah,
Hanning Nikita,
Heirbaut Jelena,
Van Remoortel Samuel,
Joossens Jurgen,
Van Der Veken Pieter,
Francque Sven M,
De bruyn Michelle,
Lambeir AnneMarie,
De Man Joris G,
Timmermans JeanPierre,
Augustyns Koen,
De Meester Ingrid,
De Winter Benedicte Y
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14396
Subject(s) - proteases , irritable bowel syndrome , tryptase , serine protease , colitis , medicine , serine , protease , pharmacology , endocrinology , chemistry , immunology , enzyme , biochemistry , mast cell
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.