Rapid in vivo clearance of C5ades arg: a possible protective mechanism against complement-mediated tissue injury.
C5ades arg is an important mediator of the tissue injury associated with intravascular complement activation and exerts its effects by causing granulocyte aggregation, leukoembolism, and oxidative damage to endothelial cells. We have now investigated some of the mechanisms responsible for deactivation of this potent complement fragment by studying the clearance of C5ades arg from the plasma of New Zealand white rabbits in vivo. Quantitative aggregation of human granulocytes was used as a bioassay for rabbit C5ades arg. After a bolus intravenous infusion of activated autologous plasma complement, athe plasma C5ades arg content peaked within 60 sec and was cleared rapidly and exponentially, with a mean half-life of 3.0 +/- 0.6 (S.E.M.) min. In neutropenic animals the half-life of C5ades arg was prolonged by 57% +/- 22 and splenectomy, but not hepatectomy, also significantly lengthened the half-life by 48% +/- 18. The most striking delay in C5ades arg clearance was induced by inhibition of endogenous proteases with EACA and aprotinin, which prolonged the half-life by 87% +/- 4 and 94% +/- 12, respectively. These data demonstrate that like other complement fragments such as C3a, C5ades arg has a very brief functional half-life in experimental animals and that although other mechanisms may be operative, endogenous proteases, circulating granulocytes, and the spleen may be important in deactivating this biologically important complement fragment. Impairment of these and other clearance mechanisms could lead to prolonged and excessive complement activation and subsequent exaggerated tissue injury.
D000380:Agranulocytosis; D000818:Animals; D002449:Cell Aggregation / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D003182:Complement C5 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015937:Complement C5a, des-Arginine; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology; D006207:Half-Life; D006498:Hepatectomy; D006801:Humans; D007700:Kinetics; D011817:Rabbits; D013156:Splenectomy
D003182:Complement C5; D015937:Complement C5a, des-Arginine