Targeting mannose-binding lectin confers long-lasting protection with a surprisingly wide therapeutic window in cerebral ischemia.
Targeting mannose-binding lectin confers long-lasting protection with a surprisingly wide therapeutic window in cerebral ischemia.
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DOI：
10.1161/circulationaha.112.103051
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发表时间：
2012-09-18
期刊：
影响因子：
37.8
通讯作者：
De Simoni MG
中科院分区：
文献类型：
--
作者：
Orsini F;Villa P;Parrella S;Zangari R;Zanier ER;Gesuete R;Stravalaci M;Fumagalli S;Ottria R;Reina JJ;Paladini A;Micotti E;Ribeiro-Viana R;Rojo J;Pavlov VI;Stahl GL;Bernardi A;Gobbi M;De Simoni MG
补体系统在脑损伤中的作用还很少被研究。在这里，我们的文件甘露糖结合凝集素（MBL），凝集素补体途径的识别分子之一，在脑缺血损伤的关键作用。在小鼠（通过永久性或短暂性大脑中动脉闭塞）和大鼠（通过3血管闭塞）中诱导局灶性脑缺血。我们首先观察到MBL在损伤后48小时沉积在缺血血管上，并且功能性MBL/MASP 2复合物增加。接下来，我们证明了：1）MBL−/−小鼠可免受短暂性和永久性缺血性损伤; 2）Polyman 2，新合成的甘露糖基化分子，因其与MBL的结合而被选择，在小鼠缺血后24小时内给药时可改善神经功能缺损和梗死体积; 3）抗MBL-A抗体在缺血后18小时内给药时可改善神经功能缺损和梗死体积，如在大鼠中28天后评估的那样。我们的数据显示MBL在脑缺血性损伤的发病机制中的重要作用，并为MBL抑制可能是人类相关治疗靶点的概念提供了强有力的支持，该靶点具有广泛的治疗应用窗口。
The involvement of complement system in brain injury has been scarcely investigated. Here we document the pivotal role of mannose binding lectin (MBL), one of the recognition molecules of the lectin complement pathway, in brain ischemic injury. Focal cerebral ischemia was induced in mice (by permanent or transient middle cerebral artery occlusion) and rats (by 3-vessels occlusion). We first observed that MBL is deposited on ischemic vessels up to 48h after injury and that functional MBL/MASP2 complexes are increased. Next we demonstrated that: 1) MBL−/− mice are protected from both transient and permanent ischemic injury; 2) Polyman2, the newly synthesized mannosylated molecule selected for its binding to MBL, improves neurological deficits and infarct volume when given up to 24h after ischemia in mice; 3) anti-MBL-A antibody improves neurological deficits and infarct volume when given up to 18h after ischemia, as assessed following 28d in rats. Our data show an important role for MBL in the pathogenesis of brain ischemic injury and provide a strong support to the concept that MBL inhibition may be a relevant therapeutic target in humans, one with a wide therapeutic window of application.