Protective effect of a human C5a receptor antagonist against hepatic ischaemia-reperfusion injury in rats.
OBJECTIVE
Complement activation is induced by ischaemia-reperfusion (I/R) and the complement factor C5a plays an important role in organ specific I/R injuries. This study investigated the efficacy of a small molecule C5a receptor (C5aR) antagonist against hepatic I/R injury.


METHODS
Total hepatic ischaemia or partial hepatic ischaemia were induced in rats, followed by a period of reperfusion. The C5aR antagonist, AcF-[OPdChaWR], was administered at 1 mg/kg i.v. or 10 mg/kg p.o. or s.c. before induction of ischaemia. Total hepatic I/R-induced mortality was measured and partial hepatic ischaemia injury was assessed by measuring the serum levels of liver enzymes, tissue or serum TNFalpha, liver and lung myeloperoxidase activity, the number of infiltrating neutrophils, neutrophilia and liver histopathology.


RESULTS
C5aR antagonist treatment reduced total hepatic I/R-induced mortality. In partial hepatic I/R rats, treatment with the C5aR antagonist significantly attenuated the increases in liver enzymes, serum and tissue TNFalpha, myeloperoxidase activity, infiltrating neutrophils, neutrophilia, and also reduced liver histopathology.


CONCLUSIONS
This study shows that an orally active, small molecule C5aR antagonist is effective in reducing the markers of tissue damage caused by I/R in the rat, suggesting an important role for C5a in I/R injuries in the liver.
Arumugam
Thiruma V
TV
Department of Physiology and Pharmacology, School of Biomedical Sciences, University of Queensland, Brisbane, Qld 4072, Australia.
Woodruff
Trent M
TM
Stocks
Shelli Z
SZ
Proctor
Lavinia M
LM
Pollitt
Sandra
S
Shiels
Ian A
IA
Reid
Robert C
RC
Fairlie
David P
DP
Taylor
Stephen M
SM
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D015936:Complement C5a / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology / Q000502:physiology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors*; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D014409:Tumor Necrosis Factor-alpha; D015936:Complement C5a; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase