Protective effect of a new C5a receptor antagonist against Ischemia-reperfusion injury in the rat small intestine

Arumugam, Thiruma V., Shiels, Ian A., Woodruff, Trent M., Reid, Robert C., Fairlie, David P. and Taylor, Stephen M. (2002) Protective effect of a new C5a receptor antagonist against Ischemia-reperfusion injury in the rat small intestine. Journal of Surgical Research, 103 2: 260-267. doi:10.1006/jsre.2002.6369


Author Arumugam, Thiruma V.
Shiels, Ian A.
Woodruff, Trent M.
Reid, Robert C.
Fairlie, David P.
Taylor, Stephen M.
Title Protective effect of a new C5a receptor antagonist against Ischemia-reperfusion injury in the rat small intestine
Journal name Journal of Surgical Research   Check publisher's open access policy
ISSN 0022-4804
1095-8673
Publication date 2002-04-01
Sub-type Article (original research)
DOI 10.1006/jsre.2002.6369
Volume 103
Issue 2
Start page 260
End page 267
Total pages 8
Place of publication London, England
Publisher Academic Press
Language eng
Subject C1
250204 Bioinorganic Chemistry
730102 Immune system and allergy
Formatted abstract
Background.
The complement system is a major contributor to the pathogenesis of intestinal ischemia–reperfusion (I/R) injury. We have studied the action of an orally active complement factor 5a (C5a) receptor antagonist, the cyclic peptide AcF-(OPdChaWR) [Ac-Phe(Orn-Pro-Image -cyclohexylalanine-Trp-Arg)] against local and remote intestinal I/R injuries in rats.

Materials and methods.
Anesthetized rats were administered with AcF-(OPdChaWR) at doses of 1 mg/kg intravenously or 0.3, 1, or 10 mg/kg orally with pyrogen-free saline for sham control animals. The superior mesenteric artery was occluded for 30 min and the intestine reperfused for 120 min. Changes associated with tissue injury were assessed by neutropenia, intestinal edema, serum tumor necrosis factor-α, serum haptoglobin, plasma aspartate aminotransferase, and histopathology.

Results.
Pretreatment with either a single intravenous dose (1 mg/kg), or a single oral dose (10 mg/kg) of AcF-(OPdChaWR) significantly inhibited I/R induced neutropenia, the elevated serum levels of tumor necrosis factor-α, haptoglobin, and plasma aspartate aminotransferase, as well as intestinal edema. Histological analysis of AcF-(OPdChaWR)-treated I/R animals showed markedly reduced mucosal layer damage compared to that of untreated rats.

Conclusions.
These results indicate that a potent antagonist of C5a receptors on human cells protects the rat small intestine from I/R injury after oral or intravenous administration. Small molecule C5a antagonists may have some therapeutic utility in reperfusion injury.
Keyword Gut Ischemia-reperfusion
C5a Receptor Antagonist
Acf-(opdchawr)
Polymorphonuclear Leukocytes
Tumor Necrosis Factor-alpha
Aspartate Aminotransferase
Haptoglobin
Edema
Tumor-necrosis-factor
Platelet-activating-factor
Complement
Protein
Anaphylatoxin
Dysfunction
Neutrophils
Expression
Cytokines
Disease
Surgery
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Biomedical Sciences Publications
 
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Created: Wed, 15 Aug 2007, 04:02:58 EST