Dexamethasone prevents visceral hyperalgesia but not colonic permeability increase induced by luminal protease-activated receptor-2 agonist in rats

Abstract

Background: Low-grade inflammation may play a role in the pathogenesis of irritable bowel syndrome (IBS). Although corticosteroids are potent inhibitors of inflammatory processes, only one study with corticosteroids in patients with postinfectious IBS exists, which suggests that prednisolone is not an effective treatment for IBS symptoms. Aim: To evaluate whether dexamethasone treatment prevents protease-activated receptor-2 (PAR-2) activation-induced visceral hyperalgesia and increased permeability in rats, and to determine whether the effects involve colonic mast cells. Methods: Abdominal contractions provoked by rectal distension were recorded in rats equipped with intramuscular electrodes. Changes in visceral hypersensitivity provoked by intracolonic administration of PAR-2-activating peptide (SLIGRL; H-serine-leucine-isoleucine-glycine-arginine-leucine-OH), changes in colonic mucosal rat mast cell protease-II (RMCP-II) content, mast cell count and PAR-2 expression were measured after a 4-day treatment with dexamethasone (1 mg/day/rat intraperitoneally) or its vehicle (water). The effect of mast cell stabiliser (doxantrazole, 1 mg/kg intraperitoneally, 2 h before and 6 h after intracolonic infusion of SLIGRL) on SLIGRL-induced visceral hyperalgesia was also assessed. The effects of SLIGRL and a mast cell degranulator (compound 48/80) on the permeability of colonic strips from vehicle-or dexamethasone-treated rats were investigated in Ussing chambers. Results: 4 days of dexamethasone as well as doxantrazole diminished the SLIGRL-induced hyperalgesia for all volumes of distension. This effect of dexamethasone was accompanied by a reduced responsiveness of colonic permeability to compound 48/80, and decreased RMCP-II content and mast cell number. Dexamethasone treatment did not influence colonic mucosal PAR-2 expression and permeability responsiveness to SLIGRL. Conclusions: Dexamethasone treatment improves PAR-2 agonist-induced visceral hypersensitivity but does not prevent PAR-2 agonist-induced increase in colonic permeability in rats. This effect is coupled with a reduction of colonic mast cell number and RMCP-II contents.

The Expression of Protease-Activated Receptor 2 and 4 in the Colon of Irritable Bowel Syndrome Patients

“…&P \ 0.001, %P \ 0.05, compared with IBS-C patients Dig Dis Sci (2012) 57:58-64 61 IBS patients or subgroups compared with control subjects. It has been reported that PAR2 expression on enterocytes is regulated by luminal serine proteases [22]. In our study, although the mRNA expressions of tryptase and trypsin were higher in IBS patients, PAR2 expression was lacking a significant difference.…”

Subjects with Diarrhea-Predominant IBS Have Increased Rectal Permeability Responsive to Tryptase

“…Other factors such as histamine, serotonin, and prostaglandins may also contribute to the increased permeability seen in IBS patients [5], and elevated colonic luminal serine protease activity of IBS-D patients could evoke a PAR-2-mediated colonic epithelial dysfunction as well [3]. This result could partially explain why dexamethasone treatment does not prevent protease-activated receptor-2 (PAR-2) agonist-induced increase in colonic permeability [25].…”

PAR-2-mediated control of barrier function and motility differs between early and late phases of postinfectious gut dysfunction in the rat

“…The A5 antibody is equivalent to the previously described B5 antiserum. A5 has been obtained in exactly the same way as B5, and both have the same specificity (2,31,32). Expression of PAR-2 was visualized using a Cy3-conjugated goat anti-rabbit secondary antibody (1 h, room temperature, 1:250, PA43004; GE Healthcare, Buckinghamshire, UK).…”