title: 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 gene-related 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.
authors.affiliation: Center for Ulcer Research and Education, Digestive Diseases Research Center, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, USA.
authors.forename: Fiore
authors.initials: F
authors.lastname: Cattaruzza
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cenac
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.forename: Mariannina
authors.initials: M
authors.lastname: Impicciatore
authors.forename: Eric
authors.initials: E
authors.lastname: Hyun
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vergnolle
authors.forename: Catia
authors.initials: C
authors.lastname: Sternini
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002211:Capsaicin / Q000494:pharmacology; D004205:Cromolyn Sodium / Q000494:pharmacology; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology*; D007413:Intestinal Mucosa / Q000098:blood supply / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2 / Q000187:drug effects / Q000378:metabolism*; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017833:Visceral Afferents / Q000187:drug effects / Q000378:metabolism
chemical_list: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides; D010446:Peptide Fragments; D012333:RNA, Messenger; D044464:Receptor, PAR-2; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; C058636:calcitonin gene-related peptide (8-37); D015740:Calcitonin Gene-Related Peptide; D004205:Cromolyn Sodium; D002211:Capsaicin