Complement inhibitors selectively attenuate injury following administration of cobra venom factor to rats.
Systemic activation of complement is a pathophysiological response common to severe disturbances such as hemorrhagic shock, major burn 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 TNFalpha 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.
Proctor
Lavinia M
LM
Promics Ltd., PO Box 4578, Eight Mile Plains, Queensland 4113, Australia. lavinia.proctor@promics.com
Strachan
Anna J
AJ
Woodruff
Trent M
TM
Mahadevan
Indumathy B
IB
Williams
H Ming
HM
Shiels
Ian A
IA
Taylor
Stephen M
SM
D000284:Administration, Oral; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002934:Cinnamates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D051056:Complement Inactivating Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D053630:Depsides; D004546:Elapid Venoms / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D007275:Injections, Intravenous; D007958:Leukocyte Count; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008171:Lung Diseases / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D015394:Molecular Structure; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors; D011951:Receptors, Complement / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097123:Rosmarinic Acid
D001120:Arginine; D001559:Benzhydryl Compounds; D002934:Cinnamates; D051056:Complement Inactivating Agents; D053630:Depsides; D004546:Elapid Venoms; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D014409:Tumor Necrosis Factor-alpha; D000097123:Rosmarinic Acid; C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); C431907:SB 290157; C016310:cobra venom factor; C085567:complement C3a receptor