Complement inhibition by hydroxychloroquine prevents placental and fetal brain abnormalities in antiphospholipid syndrome.
Complement inhibition by hydroxychloroquine prevents placental and fetal brain abnormalities in antiphospholipid syndrome.
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DOI：
10.1016/j.jaut.2016.04.008
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发表时间：
2016-12
影响因子：
12.8
通讯作者：
Girardi G
中科院分区：
文献类型：
--
作者：
Bertolaccini ML;Contento G;Lennen R;Sanna G;Blower PJ;Ma MT;Sunassee K;Girardi G
胎盘缺血性疾病和不良妊娠结局常见于抗磷脂综合征（APS）患者。尽管给予常规抗血栓治疗，但仍有相当数量的妇女继续经历不良妊娠结局，预防和管理不确定。努力开发有效的药物治疗难治性产科APS病例的策略将对母亲和胎儿都有显着的临床益处。尽管抗疟药羟氯喹（HCQ）越来越多地用于治疗患有APS的孕妇，但对HCQ的疗效和作用机制知之甚少。由于补体激活在APS的胎盘缺血和胎儿脑发育异常中起着至关重要的作用，我们假设HCQ通过抑制补体激活来预防这些妊娠并发症。使用与临床状况非常相似的产科APS小鼠模型，我们发现HCQ预防了胎儿死亡和胎盘代谢变化-通过APS小鼠的质子磁共振光谱测量。使用111 In标记的抗磷脂抗体（aPL），我们确定了胎盘和胎脑作为APS小鼠的主要器官靶点。使用相同的方法，我们发现HCQ不抑制aPL与组织的结合，如先前从体外研究中所建议的。虽然HCQ不影响aPL与胎脑的结合，但它阻止了胎脑异常皮质发育。HCQ在体内和体外阻止补体活化。来自APS患者和APS小鼠的血清样品中的补体C5 a水平在用HCQ治疗后较低，而抗体滴度保持不变。HCQ不仅防止胎盘功能不全，但也异常胎儿脑发育在APS。通过抑制补体激活，HCQ也可能是一种有效的抗血栓治疗。
Placental ischemic disease and adverse pregnancy outcomes are frequently observed in patients with antiphospholipid syndrome (APS). Despite the administration of conventional antithrombotic treatment a significant number of women continue to experience adverse pregnancy outcomes, with uncertain prevention and management. Efforts to develop effective pharmacological strategies for refractory obstetric APS cases will be of significant clinical benefit for both mothers and fetuses. Although the antimalarial drug, hydroxychloroquine (HCQ) is increasingly used to treat pregnant women with APS, little is known about its efficacy and mechanism of action of HCQ. Because complement activation plays a crucial and causative role in placental ischemia and abnormal fetal brain development in APS we hypothesised that HCQ prevents these pregnancy complications through inhibition of complement activation. Using a mouse model of obstetric APS that closely resembles the clinical condition, we found that HCQ prevented fetal death and the placental metabolic changes - measured by proton magnetic resonance spectroscopy in APS-mice. Using 111In labelled antiphospholipid antibodies (aPL) we identified the placenta and the fetal brain as the main organ targets in APS-mice. Using this same method, we found that HCQ does not inhibit aPL binding to tissues as was previously suggested from in vitro studies. While HCQ did not affect aPL binding to fetal brain it prevented fetal brain abnormal cortical development. HCQ prevented complement activation in vivo and in vitro. Complement C5a levels in serum samples from APS patients and APS-mice were lower after treatment with HCQ while the antibodies titres remained unchanged. HCQ prevented not only placental insufficiency but also abnormal fetal brain development in APS. By inhibiting complement activation, HCQ might also be an effective antithrombotic therapy.
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影响因子：
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作者：
Clowse, Megan E. B.;Magder, Laurence;Petri, Michelle
通讯作者：
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影响因子：
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作者：
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DOI：
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发表时间：
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