Inhibition of the classical and alternative pathways of the human complement system by glycosaminoglycan polysulfate

Glycosaminoglycan polysulfate (GAGPS) concentration-dependently inhibited the activation of the classical and alternative pathways of the human complement system in vitro. Concentrations of > or = 0.2 mg/ml GAGPS prevented the cleavage of C4 by human aggregated gammaglobulin as evidence of inhibition of the classical pathway. At concentrations of > or = 0.15 mg/ml a concentration-dependent inhibition of the cleavage of factor B, the major step in the activation of the alternative pathway, was seen in the presence of inulin. Concentrations < 0.05 mg/ml did not have a measurable effect on either pathway. The lysis of sheep red blood cells, which is mediated largely by the classical pathway, was significantly inhibited at 3.84 mg/ml GAGPS, with a mean inhibition of 45.7%. On the other hand, the same concentration of GAGPS almost completely inhibited the lysis of rabbit red blood cells, which is mediated by the alternative pathway of complement. Our results suggest that the inhibition by GAGPS is an early event in the activation of complement, occurring before the assembly of the C3 convertases of either pathway. The possible use of this drug in acute life-threatening situations where complement is thought to have a pathogenic role is discussed.