Please use this identifier to cite or link to this item:
http://hdl.handle.net/1942/37648
Title: | The Effect of Serine Protease Inhibitors on Visceral Pain in Different Rodent Models With an Intestinal Insult | Authors: | Ceuleers, Hannah Hanning, Nikita De Bruyn, Michelle De Man, Joris G. De Schepper, Heiko U. LI, Qian Liu, Liansheng ABRAMS, Steven Smet, Annemieke Joossens, Jurgen Augustyns, Koen De Meester, Ingrid Pasricha, Pankaj J. De Winter, Benedicte Y. |
Issue Date: | 2022 | Publisher: | FRONTIERS MEDIA SA | Source: | Frontiers in pharmacology, 13 (Art N° 765744) | Abstract: | Background: Serine proteases are believed to play a key role in the origin of abdominal pain in IBD and IBS. We previously demonstrated a reduction of visceral pain in a post-inflammatory IBS rat model after a single intraperitoneal or intracolonic administration of a serine protease inhibitor. The aim of this study was to investigate the efficacy of serine protease inhibition on visceral pain in two different animal models involving a colonic insult based either on acute inflammation or on neonatal irritation. Moreover, protease profiling was explored in the acute colitis model.Methods: An acute 2,4,6-trinitrobenzenesulphonic acid (TNBS) colitis rat model and a chronic neonatal acetic acid mouse model were used in this study. Visceral sensitivity was quantified by visceromotor responses (VMRs) to colorectal distension, 30 min after intraperitoneal administration of the serine protease inhibitors nafamostat, UAMC-00050 or their vehicles. Colonic samples from acute colitis rats were used to quantify the mRNA expression of a panel of serine proteases and mast cell tryptase by immunohistochemistry. Finally, proteolytic activities in colonic and fecal samples were characterized using fluorogenic substrates.Key Results: We showed a significant and pressure-dependent increase in visceral hypersensitivity in acute colitis and neonatal acetic acid models. UAMC-00050 and nafamostat significantly reduced VMRs in both animal models. In acute colitis rats, the administration of a serine protease inhibitor did not affect the inflammatory parameters. Protease profiling of these acute colitis animals revealed an increased tryptase immunoreactivity and a downregulation of matriptase at the mRNA level after inflammation. The administration of UAMC-00050 resulted in a decreased elastase-like activity in the colon associated with a significantly increased elastase-like activity in fecal samples of acute colitis animals.Conclusion: In conclusion, our results suggest that serine proteases play an important role in visceral hypersensitivity in an acute TNBS colitis model in rats and a neonatal acetic acid model in mice. Moreover, we hypothesize a potential mechanism of action of UAMC-00050 via the alteration of elastase-like proteolytic activity in acute inflammation. Taken together, we provided fundamental evidence for serine protease inhibitors as a promising new therapeutic strategy for abdominal pain in gastrointestinal diseases. | Notes: | Ceuleers, H (corresponding author), Univ Antwerp, Lab Expt Med & Pediat, Antwerp, Belgium.; Ceuleers, H (corresponding author), Johns Hopkins Univ, Ctr Neurogastroenterol, Dept Med, Sch Med, Baltimore, MD 21205 USA.; Ceuleers, H (corresponding author), Univ Antwerp, Ctr Excellence, Infla Med, Antwerp, Belgium. hannah.ceuleers@uantwerpen.be |
Keywords: | serine protease inhibitor;serine protease inhibitor;visceral hypersensitivity;visceral hypersensitivity;rodent models;rodent models;inflammatory bowel diseases;inflammatory bowel diseases;irritable bowel syndrome;irritable bowel syndrome;proteolytic activity;proteolytic activity;protease profiling;protease profiling | Document URI: | http://hdl.handle.net/1942/37648 | e-ISSN: | 1663-9812 | DOI: | 10.3389/fphar.2022.765744 | ISI #: | WOS:000811865200001 | Rights: | 2022 Ceuleers, Hanning, De bruyn, De Man, De Schepper, Li, Liu, Abrams, Smet, Joossens, Augustyns, De Meester, Pasricha and De Winter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2023 |
Appears in Collections: | Research publications |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
fphar-2022-765744 1..17.pdf | Published version | 2.75 MB | Adobe PDF | View/Open |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.