Protective effect of a new C5a receptor antagonist against ischemia-reperfusion injury in the rat small intestine.
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-d-cyclohexylalanine-Trp-Arg)] against local and remote intestinal I/R injuries in rats.


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-alpha, 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-alpha, 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.
Arumugam
Thiruma V
TV
Department of Physiology and Pharmacology, University of Queensland, Queensland, 4072, Australia.
Shiels
Ian A
IA
Woodruff
Trent M
TM
Reid
Robert C
RC
Fairlie
David P
DP
Taylor
Stephen M
SM
D000818:Animals; D015703:Antigens, CD; D001219:Aspartate Aminotransferases / Q000097:blood; D003250:Constriction; D004487:Edema / Q000517:prevention & control; D005260:Female; D006242:Haptoglobins / Q000032:analysis; D007410:Intestinal Diseases / Q000517:prevention & control; D007413:Intestinal Mucosa / Q000473:pathology; D007421:Intestine, Small / Q000098:blood supply* / Q000473:pathology; D017538:Mesenteric Artery, Superior; D009503:Neutropenia / Q000209:etiology / Q000517:prevention & control; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000150:complications / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D015703:Antigens, CD; D006242:Haptoglobins; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D014409:Tumor Necrosis Factor-alpha; D001219:Aspartate Aminotransferases