Wuillemin W A, te Velthuis H, Lubbers Y T, de Ruig C P, Eldering E, Hack C E
Central Laboratory of The Netherlands Red Cross Blood Transfusion Service, University of Amsterdam.
J Immunol. 1997 Aug 15;159(4):1953-60.
Activation of the complement system may contribute to the pathogenesis of many diseases. Hence, an effective inhibitor of complement might be useful to reduce tissue damage. Some glycosaminoglycans (GAG), such as heparin, are known to inhibit the interaction of C1q with activators and the assembly of the classical and the alternative pathway C3 convertases. Furthermore, they may potentiate C1 inhibitor-mediated inactivation of C1s. To search for potential complement inhibitors, we systematically investigated the complement inhibitory properties of various synthetic and naturally occurring GAG (dextran sulfates 500,000 and 5,000, heparin, N-acetylheparin, heparan sulfate, dermatan sulfate, and 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 inhibitor. 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 aggregated 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 complement activation in vitro and that the low molecular weight dextran sulfate (m.w. 5000) may be a candidate for pharmacologic manipulation of complement activation via potentiation of C1 inhibitor.
补体系统的激活可能在许多疾病的发病机制中起作用。因此，一种有效的补体抑制剂可能有助于减少组织损伤。一些糖胺聚糖（GAG），如肝素，已知可抑制C1q与激活剂的相互作用以及经典途径和替代途径C3转化酶的组装。此外，它们可能增强C1抑制剂介导的C1s失活。为了寻找潜在的补体抑制剂，我们系统地研究了各种合成和天然存在的GAG（硫酸葡聚糖500,000和5,000、肝素、N-乙酰肝素、硫酸乙酰肝素、硫酸皮肤素以及硫酸软骨素A和C）的补体抑制特性。首先，我们评估了GAG对C1抑制剂使C1s失活的二级速率常数的影响。在GAG存在下，该速率常数增加了6至130倍，硫酸葡聚糖最为有效。其次，发现所有测试的GAG都能减少C4和C3在固定化的人聚合IgG（AHG）上的沉积，并减少与AHG孵育后再钙化血浆中C4b/c和C3b/c的液相形成。再次发现硫酸葡聚糖最为有效。我们得出结论，GAG在体外调节补体激活，并且低分子量硫酸葡聚糖（分子量5000）可能是通过增强C1抑制剂对补体激活进行药理调控的候选物。
