Protective Effect of Proteinase-Activated Receptor 2 Activation on Motility Impairment and Tissue Damage Induced by Intestinal Ischemia/Reperfusion in Rodents

Abstract

We hypothesized that proteinase-activated receptor-2 (PAR 2 ) modulates intestinal injuries induced by ischemia/reperfusion. Ischemia (1 hour) plus reperfusion (6 hours) significantly delayed gastrointestinal transit (GIT) compared with sham operation. Intraduodenal injection of PAR 2 -activating peptide SLIGRL-NH 2 significantly accelerated transit in ischemia/reperfusion but not in sham-operated rats. GIT was significantly delayed in ischemia/reperfusion and sham-operated PAR 2 ؊/؊ mice compared with PAR 2 ؉/؉ . SLIGRL-NH 2 significantly accelerated transit in ischemia/reperfusion in PAR 2 ؉/؉ but not in PAR 2 ؊/؊ mice. Prevention of mast cell degranulation with cromolyn, ablation of visceral afferents with capsaicin, and antagonism of calcitonin generelated peptide (CGRP) and neurokinin-1 receptors with CGRP 8 -37 and RP67580, respectively, abolished the SLIGRL-NH 2 -induced stimulatory effect on transit in ischemia/reperfusion. Tissue damage was significantly reduced by SLIGRL-NH 2 ; this effect was not observed in cromolyn-, capsaicin-, or RP67580-treated rats but was detected following CGRP 8 -37 . Intestinal PAR 2 mRNA levels were not affected by SLIGRL-NH 2 in ischemia/reperfusion. We propose that PAR 2 modulates GIT and tissue damage in intestinal ischemia/reperfusion by a mechanism dependent on mast cells and visceral afferents. PAR 2 effect on transit might be mediated by CGRP and substance P, whereas the effect on tissue damage appears to involve substance P but not CGRP. PAR 2 might be a signaling system in the neuroimmune communication in intestinal ischemia/reperfusion.

Proinflammatory role of protease-activated receptor-2 in intestinal ischemia/reperfusion injury in rats

“…on the other hand, a recent study demonstrated that intraduodenal injection of the Par-2-activating peptide SliGrl-nH(2) may inhibit the intestinal damage and improve the delayed gastrointestinal transit induced by intestinal i/r (20). However, it remains unclear whether the functional blocking of Par-2 exacerbates intestinal i/r injury.…”

“…Several studies have reported that Par-2 mediates the protective effect against myocardiac or intestinal i/r injury (20,(40)(41)(42). These reports indicate that Par-2 activation with a Par-2-activating peptide administered to animal models reduces I/R-induced tissue damage.…”

Tempol reduces bacterial translocation after ischemia/reperfusion injury in a rat model of superior mesenteric artery occlusion

“…Previous research has shown that mesenteric I/R not only produces mucosal damage, but also induces alterations of intestinal motor activity with a delay in the gastrointestinal transit time. [30][31][32] These alterations can be the result of structural and neuronal changes occurring within the enteric nervous system, which may play a role in the progress of bacterial overgrowth with subsequent translocation caused by inadequate bacterial clearance. 30,33,34 The administration of Tempol signifi cantly decreased histological damage (Table 3) and PMN infi ltration in intestinal tissue specimens when compared with the I/ R-treated animals (group 2).…”

Activation of Protease Activated Receptor-2 Induces Delayed Cardioprotection in Anesthetized Mice

“…In a recent in vivo study examining the protective effect of SL-NH 2 against intestinal injury caused by ischemia-reperfusion, it was shown that mast cell activation was involved in the underlying mechanism of protection [7]. PAR2 is expressed on cardiac mast cells and activation leads to mast cell degranulation and the release of various biologically active mediators including TNFα [8,9].…”