The role of proteases in the pathogenesis of visceral hypersensitivity in inflammatory bowel diseases and irritable bowel syndrome
22 June 2018
UAntwerp - Campus Drie Eiken - Building O - Auditorium O7 - Universiteitsplein 1 - 2610 WILRIJK (route: UAntwerpen, Campus Drie Eiken
Prof B. De Winter, Prof I. De Meester
PhD defence Hannah Ceuleers - Faculty of Medicine and Health Sciences
Presentation in English
Visceral hypersensitivity, a mechanism underlying abdominal pain, is a major symptom in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). IBD and IBS both have an increasing prevalence, a negative impact on the quality of life and an enormous socio-economic burden. However, a curative treatment is still eagerly awaited up until today.
The available literature clearly points towards an implication of proteases in visceral hypersensitivity during IBD and IBS. Most of the studies focussed on the role of protease-activated receptors as a potential new treatment strategy for visceral pain, while direct serine protease inhibition has been investigated to a lesser extent.
Therefore, the aims of this PhD thesis were (1) to provide evidence for direct serine protease inhibition as a possible new treatment strategy for visceral pain in an TNBS-induced colitis rat model for IBD and a rat model for post-inflammatory IBS, (2) to validate a newly developed serine protease inhibitor in a neonatal acetic acid-induced mouse model and (3) to further unravel the mechanism of action of serine protease inhibitors during acute and post-inflammatory conditions.
We demonstrated a decrease in visceral hypersensitivity after the administration of the serine protease inhibitors nafamostat mesylate (commercially available), UAMC-00050 and UAMC-01162 (newly developed by the Laboratory of Medicinal Chemistry of the University of Antwerp) in an acute TNBS colitis-induced rat model for IBD and a post-inflammatory IBS rat model. Furthermore, we validated these results in an acetic acid-induced mouse model for IBS. Additionally, we examined the protease profiles involved in the pathophysiology of visceral hypersensitivity during IBD and IBS, pointing towards an important role for matriptase and tryptase in IBD and for tryptase and trypsin-3 in IBS. In order to examine the downstream signaling pathways involved in serine protease signaling, we assessed the involvement of PAR and TRP receptors with a qPCR analysis. mRNA expression of PAR4 (colon and DRG T13-L2) and TRPA1 (DRG T13-L2) were significantly upregulated in post-colitis animals. Besides, PAR2 and TRPA1 immunoreactivity co-localized with CGRP-positive nerve fibers in control and post-colitis animals. Accordingly, trypsin-like activity was significantly increased in the colon but not in the feces. Fecal protease activity, assessed by an azocasein assay, was significantly increased in acute colitis and post-colitis animals compared to controls.
From these results we conclude that direct serine protease inhibition might encompass an interesting new treatment strategy for visceral pain in IBD and IBS patients.