Complement inhibitors selectively attenuate injury following administration of cobra venom factor to rats

Proctor, Lavinia M., Strachan, Anna J., Woodruff, Trent M., Mahadevan, Indumathy B., Williams, H. Ming, Shiels, Ian A. and Taylor, Stephen M. (2006) Complement inhibitors selectively attenuate injury following administration of cobra venom factor to rats. International Immunopharmacology, 6 8: 1224-1232. doi:10.1016/j.intimp.2006.03.002


Author Proctor, Lavinia M.
Strachan, Anna J.
Woodruff, Trent M.
Mahadevan, Indumathy B.
Williams, H. Ming
Shiels, Ian A.
Taylor, Stephen M.
Title Complement inhibitors selectively attenuate injury following administration of cobra venom factor to rats
Journal name International Immunopharmacology   Check publisher's open access policy
ISSN 1567-5769
1878-1705
Publication date 2006-08-01
Sub-type Article (original research)
DOI 10.1016/j.intimp.2006.03.002
Volume 6
Issue 8
Start page 1224
End page 1232
Total pages 9
Place of publication Amsterdam, The Netherlands
Publisher Elsevier Science
Language eng
Subject C1
0304 Medicinal and Biomolecular Chemistry
1115 Pharmacology and Pharmaceutical Sciences
Formatted abstract
Systemic activation of complement is a pathophysiological response common to severe disturbances such as hemorrhagic shock, major bum injury and sepsis. Intravenous infusion of cobra venom factor (CVF) has been used as an animal model of acute respiratory distress syndrome (ARDS), and reliably and selectively induces rapid intravascular activation of the complement system, leading to acute organ damage. In the present study, we have used different complement inhibitors to investigate the roles of complement products in CVF-induced responses in the rat. Rats were treated with either a C5a receptor antagonist (C5aRA, AcF-[OP(D-Cha)WR], 1 mg/kg i.v. or 10 mg/kg p.o.), a C3a receptor antagonist (C3aRA, N(2)-[(2,2-diphenylethoxy)acetyl]-L-arginine, 0.1 mg/kg i.v.) or a convertase inhibitor, rosmarinic acid (RMA, 10 mg/kg i.v.), prior to CVF-induced complement challenge. Intravenous CVF resulted in hallmark events evident in the development of ARDS, including systemic neutropenia followed by neutrophil migration to the lung and bronchoalveolar vascular leakage, blood pressure alterations, and an increase in TNF alpha levels in both serum and bronchoalveolar lavage fluid. These hemodynamic changes were differentially inhibited by antagonism of C5a receptors, C3a receptors or by inhibition of the entire complement cascade using RMA. This evidence strongly implicates complement factors in the development of lung injury associated with systemic complement activation and identifies complement inhibition as a potential therapeutic target for acute syndromes such as ARDS and other severe systemic shock states mediated by activation of complement.
Copyright © 2006 Elsevier B.V. All rights reserved.
Keyword Immunology
Pharmacology & Pharmacy
Complement
Cobra Venom Factor
C3a
C5a
C5a Antagonist
C5a Receptor Antagonist
Ischemia-reperfusion Injury
C3a Receptor
Intravascular Activation
Systemic Activation
Rosmarinic Acid
Lung Injury
Anaphylatoxin
Potent
Inflammation
Acute Lung Injury
Q-Index Code C1

 
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Created: Wed, 15 Aug 2007, 18:33:06 EST