Ferrara Dardo E, Liu Xiaowei, Espinola Ricardo G, Meroni Pier Luigi, Abukhalaf Imad, Harris E Nigel, Pierangeli Silvia S
Morehouse School of Medicine, Atlanta, Georgia 30310-1495, USA.
Arthritis Rheum. 2003 Nov;48(11):3272-9. doi: 10.1002/art.11449.
Antiphospholipid antibodies (aPL) have thrombogenic properties in vivo, through their interactions with soluble coagulation factors and their ability to modulate the functions of cells involved in coagulation homeostasis. These antibodies have also been shown to enhance the adhesion of leukocytes to endothelial cells (ECs) in vivo. New lipophilic statins such as fluvastatin have antiinflammatory and antithrombogenic effects. This study uses an in vivo mouse model to investigate whether fluvastatin has an effect on decreasing both the adhesion of leukocytes to ECs and the thrombus formation induced by aPL.
Two groups of CD-1 male mice, each comprising approximately 18 mice, were fed either normal saline solution or 15 mg/kg fluvastatin for 15 days. Each of the 2 groups was further subdivided to receive either purified IgG from patients with the antiphospholipid syndrome (IgG-APS) or normal IgG from healthy subjects. Analysis of thrombus dynamics was performed in treated and control mice, using a standardized thrombogenic injury procedure, and the area (size) of the thrombus was measured. Adhesion of leukocytes to ECs was analyzed with a microcirculation model of exposed cremaster muscle. Baseline and posttreatment soluble intercellular adhesion molecule 1 (sICAM-1) levels were determined by enzyme-linked immunosorbent assay.
IgG-APS mice treated with fluvastatin showed significantly smaller thrombi, a reduced number of adherent leukocytes, and decreased levels of sICAM-1 compared with IgG-APS animals treated with placebo.
These findings indicate that fluvastatin significantly diminishes aPL-mediated thrombosis and EC activation in vivo. These results may have important implications for the design of new treatment strategies aimed at preventing recurrent thrombosis in patients with APS.
抗磷脂抗体（aPL）在体内具有致血栓形成特性，通过其与可溶性凝血因子的相互作用以及调节参与凝血稳态的细胞功能的能力。这些抗体在体内还被证明可增强白细胞与内皮细胞（ECs）的黏附。新型亲脂性他汀类药物如氟伐他汀具有抗炎和抗血栓形成作用。本研究使用体内小鼠模型来研究氟伐他汀是否对降低白细胞与ECs的黏附以及aPL诱导的血栓形成均有影响。
两组CD-1雄性小鼠，每组约18只，分别给予生理盐水溶液或15mg/kg氟伐他汀，持续15天。两组中的每一组再进一步细分，分别接受来自抗磷脂综合征患者的纯化IgG（IgG-APS）或来自健康受试者的正常IgG。使用标准化的致血栓形成损伤程序，对治疗组和对照组小鼠进行血栓动力学分析，并测量血栓面积（大小）。用暴露的提睾肌微循环模型分析白细胞与ECs的黏附。通过酶联免疫吸附测定法测定基线和治疗后可溶性细胞间黏附分子1（sICAM-1）水平。
与接受安慰剂治疗的IgG-APS动物相比，接受氟伐他汀治疗的IgG-APS小鼠血栓明显更小，黏附的白细胞数量减少，sICAM-1水平降低。
这些发现表明氟伐他汀在体内可显著减少aPL介导的血栓形成和EC活化。这些结果可能对旨在预防APS患者复发性血栓形成的新治疗策略设计具有重要意义。
