A new small molecule C5a receptor antagonist inhibits the reverse-passive Arthus reaction and endotoxic shock in rats.
C5a is implicated as a pathogenic factor in a wide range of immunoinflammatory diseases, including sepsis and immune complex disease. Agents that antagonize the effects of C5a could be useful in these diseases. We have developed some novel C5a antagonists and have determined the acute anti-inflammatory properties of a new small molecule C5a receptor antagonist against C5a- and LPS-induced neutrophil adhesion and cytokine expression, as well as against some hallmarks of the reverse Arthus reaction in rats. We found that a single i.v. dose (1 mg/kg) of this antagonist inhibited both C5a- and LPS-induced neutropenia and elevated levels of circulating TNF-alpha, as well as polymorphonuclear leukocyte migration, increased TNF-alpha levels and vascular leakage at the site of immune complex deposition. These results indicate potent anti-inflammatory activities of a new C5a receptor antagonist and provide more evidence for a key early role for C5a in sepsis and the reverse Arthus reaction. The results support a role for antagonists of C5a receptors in the therapeutic intervention of immunoinflammatory disease states such as sepsis and immune complex disease.
Strachan
A J
AJ
Department of Physiology and Pharmacology, and Drug, Design and Development Centre, University of Queensland, St. Lucia, Australia.
Woodruff
T M
TM
Haaima
G
G
Fairlie
D P
DP
Taylor
S M
SM
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism; D001183:Arthus Reaction / Q000276:immunology / Q000517:prevention & control*; D001202:Ascitic Fluid / Q000276:immunology / Q000517:prevention & control; D001667:Binding, Competitive / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D015936:Complement C5a / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012772:Shock, Septic / Q000276:immunology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000093242:Interleukin-6 Inhibitors
D015703:Antigens, CD; D015936:Complement C5a; D003169:Complement Inactivator Proteins; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C114186:cyclo(acetylphenylalanyl-ornithyl-prolyl-cyclohexylalanyl-tryptophyl-arginyl)