Protective effect of a human C5a receptor antagonist against hepatic ischaemia-reperfusion injury in rats

Arumugam, Thiruma V., Woodruff, Trent M., Stocks, Shelli Z., Proctor, Lavinia M., Pollitt, Sandra, Shiels, Ian A., Reid, Robert C., Fairlie, David P., Taylor, Stephen M. and M. Colombo (2004) Protective effect of a human C5a receptor antagonist against hepatic ischaemia-reperfusion injury in rats. Journal of Hepatology, 40 6: 934-941. doi:10.1016/j.jhep.2004.02.017


Author Arumugam, Thiruma V.
Woodruff, Trent M.
Stocks, Shelli Z.
Proctor, Lavinia M.
Pollitt, Sandra
Shiels, Ian A.
Reid, Robert C.
Fairlie, David P.
Taylor, Stephen M.
M. Colombo
Title Protective effect of a human C5a receptor antagonist against hepatic ischaemia-reperfusion injury in rats
Journal name Journal of Hepatology   Check publisher's open access policy
ISSN 0168-8278
Publication date 2004-06-01
Sub-type Article (original research)
DOI 10.1016/j.jhep.2004.02.017
Volume 40
Issue 6
Start page 934
End page 941
Total pages 8
Place of publication Amsterdam, The Netherlands
Publisher Elsevier
Language eng
Subject C1
320599 Pharmacology not elsewhere classified
730102 Immune system and allergy
Formatted abstract
Background/Aims:
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.
Keyword C5a Receptor Antagonist
Hepatic Ischaemia Reperfusion
Myeloperoxidase
Tumor Necrosis Factor Alpha
Inflammation
Necrosis-factor-alpha
Kupffer Cells
Ischemia/reperfusion Injury
Neutrophil Activation
Liver-injury
Complement Activation
Inflammatory Response
Superoxide Generation
Beta(2) Integrins
In-vivo
Gastroenterology & Hepatology
Q-Index Code C1

 
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Created: Wed, 15 Aug 2007, 14:54:44 EST