Protective effect of proteinase-activated receptor 2 activation on motility impairment and tissue damage induced by intestinal ischemia/reperfusion in rodents

Am J Pathol. 2006 Jul;169(1):177-88. doi: 10.2353/ajpath.2006.051098.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcitonin Gene-Related Peptide / pharmacology
  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Capsaicin / pharmacology
  • Cromolyn Sodium / pharmacology
  • Female
  • Gastrointestinal Motility / drug effects
  • Gastrointestinal Motility / physiology*
  • Intestinal Mucosa / blood supply
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / pathology*
  • Male
  • Mast Cells / drug effects
  • Mast Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Neurokinin-1 Receptor Antagonists
  • Oligopeptides / pharmacology
  • Peptide Fragments / pharmacology
  • RNA, Messenger / analysis
  • Rats
  • Rats, Wistar
  • Receptor, PAR-2 / drug effects
  • Receptor, PAR-2 / metabolism*
  • Reperfusion Injury / pathology
  • Reperfusion Injury / physiopathology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Visceral Afferents / drug effects
  • Visceral Afferents / metabolism


  • Calcitonin Gene-Related Peptide Receptor Antagonists
  • Neurokinin-1 Receptor Antagonists
  • Oligopeptides
  • Peptide Fragments
  • RNA, Messenger
  • Receptor, PAR-2
  • seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide
  • calcitonin gene-related peptide (8-37)
  • Calcitonin Gene-Related Peptide
  • Cromolyn Sodium
  • Capsaicin