Protective effect of proteinase-activated receptor 2 activation on motility impairment and tissue damage induced by intestinal ischemia/reperfusion in rodents.
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.
Cattaruzza
Fiore
F
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.
Cenac
Nicolas
N
Barocelli
Elisabetta
E
Impicciatore
Mariannina
M
Hyun
Eric
E
Vergnolle
Nathalie
N
Sternini
Catia
C
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
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