POTENTIATION OF C1 INHIBITOR BY GLYCOSAMINOGLYCANS - DEXTRAN SULFATE SPECIES ARE EFFECTIVE INHIBITORS OF IN-VITRO COMPLEMENT ACTIVATION IN PLASMA

Activation of the complement system may contribute to the pathogenesis of many diseases. Hence, an effective inhibitor of complement might b e useful to reduce tissue damage. Some glycosaminoglycans (GAG), such as heparin, are known to inhibit the interaction of Clq with activator s and the assembly of the classical and the alternative pathway C3 con vertases. Furthermore, they may potentiate C1 inhibitor-mediated inact ivation of Cls. To search for potential complement inhibitors, we syst ematically investigated the complement inhibitory properties of variou s synthetic and naturally occurring GAG (dextran sulfates 500,000 and 5,000, heparin, N-acetylheparin, heparan sulfate, dermatan sulfate, an d chondroitin sulfates A and C). First, we assessed the effect of GAG on the second-order rate constant of the inactivation of C1s by C1 inh ibitor. This rate constant increased 6- to 130-fold in the presence of the GAG, dextran sulfate being the most effective. Second, all tested GAG were found to reduce deposition of C4 and C3 on immobilized aggre gated human IgG (AHG) and to reduce fluid phase formation of C4b/c and C3b/c in recalcified plasma upon incubation with AHG. Dextran sulfate again was found to be most effective. We conclude that GAG modulate c omplement activation in vitro and that the low molecular weight dextra n sulfate (m.w. 5000) may be a candidate for pharmacologic manipulatio n of complement activation via potentiation of C1 inhibitor.