Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury
Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury
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DOI：
10.1073/pnas.1101748108
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发表时间：
2011-05-03
影响因子：
11.1
通讯作者：
Stover, Cordula M.
中科院分区：
文献类型：
--
作者：
Schwaeble, Wilhelm J.;Lynch, Nicholas J.;Stover, Cordula M.
补体研究经历了第三个激活途径，凝集素途径的发现复兴。我们开发了一种独特的总凝集素途径缺陷模型，即缺乏甘露聚糖结合凝集素相关丝氨酸蛋白酶-2（MASP-2）的小鼠品系，并分析了MASP-2在两种缺血后再灌注损伤（IRI）模型中的作用。在瞬时心肌IRI的模型中，MASP-2缺陷型小鼠的梗死体积显著小于其野生型同窝仔。缺乏下游补体成分C4的小鼠没有受到保护，这表明存在以前未描述的凝集素途径依赖性C4旁路。在体外证明了在不存在C4的情况下凝集素途径介导的C3活化，并显示需要MASP-2、C2和MASP-1/3。MASP-2缺陷也保护小鼠免受胃肠道IRI，MASP-2的基于mAb的抑制剂也是如此。在该实验模型中MASP-2抑制的治疗效果表明抗MASP-2抗体疗法在再灌注损伤和其它凝集素途径介导的病症中的效用。
Complement research experienced a renaissance with the discovery of a third activation route, the lectin pathway. We developed a unique model of total lectin pathway deficiency, a mouse strain lacking mannan-binding lectin-associated serine protease-2 (MASP-2), and analyzed the role of MASP-2 in two models of postischemic reperfusion injury (IRI). In a model of transient myocardial IRI, MASP-2-deficient mice had significantly smaller infarct volumes than their wild-type littermates. Mice deficient in the downstream complement component C4 were not protected, suggesting the existence of a previously undescribed lectin pathway-dependent C4-bypass. Lectin pathway-mediated activation of C3 in the absence of C4 was demonstrated in vitro and shown to require MASP-2, C2, and MASP-1/3. MASP-2 deficiency also protects mice from gastrointestinal IRI, as do mAb-based inhibitors of MASP-2. The therapeutic effects of MASP-2 inhibition in this experimental model suggest the utility of anti-MASP-2 antibody therapy in reperfusion injury and other lectin pathway-mediated disorders.