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(American Journal of Pathology. 2006;169:177-188.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051098

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

Fiore Cattaruzza*{dagger}, Nicolas Cenac{ddagger}, Elisabetta Barocelli§, Mariannina Impicciatore§, Eric Hyun{ddagger}, Nathalie Vergnolle{ddagger} and Catia Sternini*{dagger}

From the Center for Ulcer Research and Education, Digestive Diseases Research Center,* Division of Digestive Diseases, Departments of Medicine and Neurobiology, David Geffen School of Medicine University of California, Los Angeles, California; the Veterans Affairs Greater Los Angeles Health System,{dagger} Los Angeles, California; the Department of Pharmacology and Therapeutics,{ddagger} University of Calgary, Calgary, Alberta, Canada; and the Department of Pharmacological, Biological and Applied Chemical Sciences,§ University of Parma, Parma, Italy

We hypothesized that proteinase-activated receptor-2 (PAR2) 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 PAR2-activating peptide SLIGRL-NH2 significantly accelerated transit in ischemia/reperfusion but not in sham-operated rats. GIT was significantly delayed in ischemia/reperfusion and sham-operated PAR2–/– mice compared with PAR2+/+. SLIGRL-NH2 significantly accelerated transit in ischemia/reperfusion in PAR2+/+ but not in PAR2–/– mice. Prevention of mast cell degranulation with cromolyn, ablation of visceral afferents with capsaicin, and antagonism of calcitonin gene-related peptide (CGRP) and neurokinin-1 receptors with CGRP8–37 and RP67580, respectively, abolished the SLIGRL-NH2-induced stimulatory effect on transit in ischemia/reperfusion. Tissue damage was significantly reduced by SLIGRL-NH2; this effect was not observed in cromolyn-, capsaicin-, or RP67580-treated rats but was detected following CGRP8–37. Intestinal PAR2 mRNA levels were not affected by SLIGRL-NH2 in ischemia/reperfusion. We propose that PAR2 modulates GIT and tissue damage in intestinal ischemia/reperfusion by a mechanism dependent on mast cells and visceral afferents. PAR2 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. PAR2 might be a signaling system in the neuroimmune communication in intestinal ischemia/reperfusion.




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