Newly developed serine protease inhibitors decrease visceral hypersensitivity in a post‐inflammatory rat model for irritable bowel syndrome

Ceuleers, Hannah; Hanning, Nikita; Heirbaut, Jelena; Remoortel, Samuel Van; Joossens, Jurgen; Veken, Pieter Van der; Francque, Sven; bruyn, Michelle De; Lambeir, Anne‐Marie; Man, Joris G. De; Timmermans, Jean‐Pierre; Augustyns, Koen; Meester, Ingrid De; Winter, Benedicte Y. De

doi:10.1111/bph.14396

Cited by 33 publications

(75 citation statements)

References 58 publications

(82 reference statements)

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“…Therefore, our finding that Mrgprc11 can be considered a mediator of visceral hypersensitivity opens new directions to explore its role in protease-mediated signaling in the bowel, especially given the importance of such signaling pathways in chronic abdominal pain disorders. [45][46][47][48] In conclusion, our results point out a novel role for Mrgprc11 in gut nociception, where receptor activation induces visceral hypersensitivity in healthy mice. This strengthens the hypothesis that Mrgprs in general play a pivotal role in gut nociception.…”

Section: Discussionmentioning

confidence: 52%

“…In the gut, these PAR‐2 agonists, among other effects, impact on gut nociception and cause visceral hypersensitivity through PAR‐2 signaling, but whether these agonists can mediate effects through Mrgprc11 is currently unknown. Therefore, our finding that Mrgprc11 can be considered a mediator of visceral hypersensitivity opens new directions to explore its role in protease‐mediated signaling in the bowel, especially given the importance of such signaling pathways in chronic abdominal pain disorders …”

Section: Discussionmentioning

confidence: 99%

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Mas‐related G protein‐coupled receptor C11 (Mrgprc11) induces visceral hypersensitivity in the mouse colon: A novel target in gut nociception?

Remoortel

Ceuleers

Arora

et al. 2019

Neurogastroenterology Motil

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Background Visceral hypersensitivity, an important cause of abdominal pain in disorders such as IBD and IBS, presents with a poorly understood pathophysiology and limited treatment options. Several members of the Mas‐related G protein‐coupled receptor family (Mrgprs) have become promising targets in pain research. The potential link between the murine Mrgpr C11 (Mrgprc11) and gut nociception is currently uninvestigated. Therefore, we explored the expression and functional role of Mrgprc11 in the gut nociceptive innervation. Methods Mrgprc11 expression was evaluated in DRG neurons innervating the mouse colon using in situ hybridization and immunohistochemistry. Visceromotor responses to colorectal distension (CRD) assessed the effect of the Mrgprc11 agonist, BAM(8‐22), on colonic pain sensitivity in healthy mice. Moreover, we determined pERK1/2‐immunoreactivity in the thoracolumbar spinal cord after noxious CRD. Finally, from a translational point of view, we looked for expression of the human counterpart of Mrgprc11, MRGPRX1, in human thoracolumbar DRGs. Key Results In situ hybridization and immunohistochemistry revealed Mrgprc11 expression in colonic DRG neurons. Intracolonic administration of BAM(8‐22) significantly increased colonic pain sensitivity in an Mrgprc11‐dependent manner, and led to a significantly increased degree of neuronal activation in the splanchnic spinal cord upon noxious stimulation. Furthermore, MRGPRX1 expression was also detected in human thoracolumbar DRG neurons. Conclusions & Inferences Our findings established a novel function for Mrgprc11 in the gut nociceptive innervation and propose the receptor as a new player in visceral hypersensitivity. Given the presence of MRGPRX1 in human DRG neurons, our study warrants future research on its therapeutic potential in abdominal pain disorders.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Mas‐related G protein‐coupled receptor C11 (Mrgprc11) induces visceral hypersensitivity in the mouse colon: A novel target in gut nociception?

Remoortel

Ceuleers

Arora

et al. 2019

Neurogastroenterology Motil

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“…Additional details on dose titration for inhibitors is provided in online supplementary methods. Additionally, trypsin-like, chymotrypsin-like, neutrophil elastase, pancreatic elastase and kallikrein PAs were determined using their respective substrates N-p-Tosyl-Gly-Pro-Arg 7-amido-methylcoumarin HCl (AMC),26 Suc-Ala-Ala-Pro-Phe-AMC,27 Suc-Ala-Ala-Pro-Val-AMC,28 Suc-Ala-Ala-Ala-AMC29 and Pro-Phe-Arg-AMC 30 31. The faecal supernatants were mixed with 100 µM substrate solution in 50 mM Tris-HCl pH 8.0 containing 10 mM CaCl2 in a microtitre plate.…”

Section: Methodsmentioning

confidence: 99%

Serine proteases as luminal mediators of intestinal barrier dysfunction and symptom severity in IBS

Edogawa

Edwinson

Peters

et al. 2019

Gut

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ObjectiveThe intestinal lumen contains several proteases. Our aim was to determine the role of faecal proteases in mediating barrier dysfunction and symptoms in IBS.Design39 patients with IBS and 25 healthy volunteers completed questionnaires, assessments of in vivo permeability, ex vivo colonic barrier function in Ussing chambers, tight junction (TJ) proteins, ultrastructural morphology and 16 s sequencing of faecal microbiota rRNA. A casein-based assay was used to measure proteolytic activity (PA) in faecal supernatants (FSNs). Colonic barrier function was determined in mice (ex-germ free) humanised with microbial communities associated with different human PA states.ResultsPatients with IBS had higher faecal PA than healthy volunteers. 8/20 postinfection IBS (PI-IBS) and 3/19 constipation- predominant IBS had high PA (>95th percentile). High-PA patients had more and looser bowel movements, greater symptom severity and higher in vivo and ex vivo colonic permeability. High-PA FSNs increased paracellular permeability, decreased occludin and increased phosphorylated myosin light chain (pMLC) expression. Serine but not cysteine protease inhibitor significantly blocked high-PA FSN effects on barrier. The effects on barrier were diminished by pharmacological or siRNA inhibition of protease activated receptor-2 (PAR-2). Patients with high-PA IBS had lower occludin expression, wider TJs on biopsies and reduced microbial diversity than patients with low PA. Mice humanised with high-PA IBS microbiota had greater in vivo permeability than those with low-PA microbiota.ConclusionA subset of patients with IBS, especially in PI-IBS, has substantially high faecal PA, greater symptoms, impaired barrier and reduced microbial diversity. Commensal microbiota affects luminal PA that can influence host barrier function.

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“…In a recent study, the serine protease inhibitor UAMC-00050 was evaluated in an in vivo model of DED. 46 UAMC-00050, a small diphenyl phosphonate with a multi-target inhibition profile, 47 , 48 was administered as eye drops in rats subjected to the removal of the exorbital lacrimal gland. UAMC-00050 induced a significant reduction in ocular surface damage, a decrement of IL-1α and TNF-α levels in tear fluid, although it did not exert any effect on tear volume.…”

Section: Novel Emerging Therapies For Ded With Anti-inflammatory Propmentioning

confidence: 99%

Experimental Pharmacotherapy for Dry Eye Disease: A Review

Baiula¹,

Spampinato²

2021

JEP

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Dry eye disease (DED) is a complex multifactorial disease showing heterogenous symptoms, including dryness, photophobia, ocular discomfort, irritation and burning but also pain. These symptoms can affect visual function leading to restrictions in daily life activities and reduction in work productivity with a consequently high impact on quality of life. Several pathological mechanisms contribute to the disease: evaporative water loss leads to impairment and loss of tear homeostasis inducing either directly or indirectly to inflammation, in a self-perpetuating vicious cycle. Dysregulated ocular immune responses result in ocular surface damage, which further contributes to DED pathogenesis. Currently, DED treatment is based on a flexible stepwise approach to identify the most beneficial intervention. Although most of the available treatments may control to a certain extent some signs and symptoms of DED, they show significant limitations and do not completely address the needs of patients suffering from DED. This review provides an overview of the emerging experimental therapies for DED. Several promising therapeutic strategies are under development with the aim of dampening inflammation and restoring the homeostasis of the ocular surface microenvironment. Results from early phase clinical trials, testing the effects of EnaC blockers, TRPM8 agonist or mesenchymal stem cells in DED patients, are especially awaited to demonstrate their therapeutic value for the treatment of DED. Moreover, the most advanced experimental strategies in the pipeline for DED, tivanisiran, IL-1R antagonist EBI-005 and SkQ1, are being tested in Phase III clinical trials, still ongoing. Nevertheless, although promising results, further studies are still needed to confirm efficacy and safety of the new emerging therapies for DED.

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Newly developed serine protease inhibitors decrease visceral hypersensitivity in a post‐inflammatory rat model for irritable bowel syndrome

Cited by 33 publications

References 58 publications

Mas‐related G protein‐coupled receptor C11 (Mrgprc11) induces visceral hypersensitivity in the mouse colon: A novel target in gut nociception?

Mas‐related G protein‐coupled receptor C11 (Mrgprc11) induces visceral hypersensitivity in the mouse colon: A novel target in gut nociception?

Serine proteases as luminal mediators of intestinal barrier dysfunction and symptom severity in IBS

Experimental Pharmacotherapy for Dry Eye Disease: A Review

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