Edens R E, Linhardt R J, Bell C S, Weiler J M
Iowa City VA Medical Center, University of Iowa Hospitals and Clinics 52242.
Immunopharmacology. 1994 Mar-Apr;27(2):145-53. doi: 10.1016/0162-3109(94)90049-3.
Heparin has been shown to inhibit activity of the alternative, classical and terminal pathways of complement by regulating C1, C1 inhibitor, C4 binding protein, C3b, factor H and S-protein. In vivo, heparin inhibits cobra venom factor activation of complement in a dose-related manner in guinea pigs. However, the ability of heparin and of modified heparin to inhibit complement activation in serum has not been examined systematically. The present study compared commercial heparin with a modified heparin that has reduced anticoagulant activity (N-desulfated, N-acetylated heparin) for ability to inhibit cobra venom factor and zymosan-induced complement activation in guinea pig and human serum. Both heparins inhibited cobra venom factor and zymosan-induced consumption of C3 activity in both human and guinea pig serum. In both serum types, commercial heparin was about twice as active as modified heparin on a weight basis for ability to inhibit cobra venom factor-induced complement activation. Both heparins also inhibited zymosan-induced complement activation in human serum. About four times more heparin was required to inhibit cobra venom factor-induced complement activation in guinea pig serum than in human serum while heparin was more than ten times more active in human serum than in guinea pig serum when zymosan was used as the activator of complement. This study suggests that heparin is considerably more effective in regulating complement activity in humans than in guinea pigs, an animal model in which heparin clearly has in vivo capacity to regulate complement activity. These observations represent an important step in the development of new clinically relevant oligosaccharide-derived pharmacologic agents to regulate complement activity.
肝素已被证明可通过调节C1、C1抑制剂、C4结合蛋白、C3b、因子H和S蛋白来抑制补体替代途径、经典途径和终末途径的活性。在体内，肝素在豚鼠中以剂量相关的方式抑制眼镜蛇毒因子激活补体。然而，肝素和修饰肝素抑制血清中补体激活的能力尚未得到系统研究。本研究比较了商业肝素与抗凝活性降低的修饰肝素（N-去硫酸化、N-乙酰化肝素）在抑制豚鼠和人血清中眼镜蛇毒因子和酵母聚糖诱导的补体激活方面的能力。两种肝素均抑制人血清和豚鼠血清中眼镜蛇毒因子和酵母聚糖诱导的C3活性消耗。在两种血清类型中，以重量计，商业肝素在抑制眼镜蛇毒因子诱导的补体激活方面的活性约为修饰肝素的两倍。两种肝素还抑制人血清中酵母聚糖诱导的补体激活。抑制豚鼠血清中眼镜蛇毒因子诱导的补体激活所需的肝素量约是人血清中的四倍，而当酵母聚糖用作补体激活剂时，肝素在人血清中的活性比在豚鼠血清中高十多倍。这项研究表明，肝素在调节人类补体活性方面比在豚鼠中更有效，而在豚鼠这种动物模型中，肝素显然具有体内调节补体活性的能力。这些观察结果代表了开发新型临床相关寡糖衍生药理剂以调节补体活性的重要一步。
