A non-anticoagulant synthetic pentasaccharide reduces inflammation in a murine model of kidney ischemia-reperfusion injury
A non-anticoagulant synthetic pentasaccharide reduces inflammation in a murine model of kidney ischemia-reperfusion injury
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DOI：
10.1160/th06-07-0418
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发表时间：
2006-12-01
影响因子：
6.7
通讯作者：
Mackman, Nigel
中科院分区：
文献类型：
--
作者：
Frank, Rolf Dario;Holscher, Todd;Mackman, Nigel
磺达肝癸钠是一种合成五糖，以抗凝血酶依赖性方式选择性抑制因子Xa（FXa）。这种新开发的抗凝剂用于预防和治疗静脉血栓栓塞。最近，我们发现磺达肝癸钠可减轻炎症并保护肾脏免受缺血再灌注（I/R）损伤。然而，磺达肝癸钠的抗凝和抗炎活性对观察到的保护作用的相对贡献尚不清楚。为了解决这个问题，我们化学修饰磺达肝癸钠，以消除其对抗凝血酶的亲和力，并分析了这种非抗凝血（NAC）-五糖在体外对U937细胞与P-选择素结合的影响，以及对肾I/R损伤小鼠模型中炎症的影响。NAC-五糖在抑制U937细胞与P-选择素结合方面与磺达肝癸钠一样有效。此外，NAC-五糖显著降低了肾I/R模型中IL-6和MIP-2的表达和损伤。这些发现表明磺达肝癸钠的抗炎活性可以与其抗凝活性分离，NAC-五糖在肾I/R损伤中具有保护作用。
Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa (FXa) in an antithrombin-dependent fashion. This newly developed anticoagulant is used in the prevention and treatment of venous thromboembolism. Recently, we showed that fondaparinux reduces inflammation and protects the kidney from ischemia-reperfusion (I/R) injury. However, the relative contributions of the anticoagulant and anti-inflammatory activities of fondaparinux to the observed protection is unknown. To address this, we chemically modified fondaparinux to abolish its affinity for antithrombin and analyzed the effect of this non-anti-coagulant (NAC)-pentasaccharide on binding of U937 cells to P-selectin in vitro and on inflammation in a murine model of kidney I/R injury. NAC-pentasaccharide was as effective as fondaparinux at inhibiting the binding of U937 cells to P-selectin. In addition, NAC-pentasaccharide significantly reduced IL-6 and MIP-2 expression and injury in the kidney I/R model. These findings indicate that the anti-inflammatory activity of fondaparinux can be dissociated from its anticoagulant activity and that NAC-pentasaccharide is protective in kidney I/R injury.