Inhibition of mannose-binding lectin reduces postischemic myocardial reperfusion injury
Inhibition of mannose-binding lectin reduces postischemic myocardial reperfusion injury
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DOI：
10.1161/hc3601.095578
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发表时间：
2001-09-18
期刊：
影响因子：
37.8
通讯作者：
Stahl, GL
中科院分区：
文献类型：
--
作者：
Jordan, JE;Montalto, MC;Stahl, GL
背景-补体由参与先天免疫和适应性免疫的蛋白质的复杂级联组成。该级联可以通过3种不同的机制激活，称为经典途径、替代途径和凝集素途径。虽然补体被广泛接受为参与缺血再灌注损伤的病理生理学，凝集素途径的具体作用尚未addressed.Methods和Results-Monoclonal antibodies（单克隆抗体; P7 E4和14C3.74，IgG 1 κ同种型）提出了对大鼠甘露糖结合凝集素（rMBL）。两种单克隆抗体通过Western分析或表面等离子体共振识别rMBL-A。P7 E4，而不是14C3.74，表现出浓度依赖性的凝集素途径的抑制，在10 μ g/mL的最大效果。在体内，大鼠进行30分钟的左冠状动脉闭塞和4小时的再灌注。与14C3.74处理的心脏相比，用P7 E4预处理的心脏中的补体C3沉积大大减弱。与14C3.74处理的动物相比，用P7 E4（1 mg/kg）预处理显著减少心肌肌酸激酶损失（48%）、梗死面积（39%）和中性粒细胞浸润（47%）。此外，P7 E4预处理显着衰减的表达促炎基因（细胞间粘附分子-1，血管细胞粘附分子-1，和白细胞介素-6）后ischemia-reperfusion. Conclusions凝集素补体途径激活心肌缺血-再灌注，并导致组织损伤。用抑制性单克隆抗体阻断凝集素途径通过减少中性粒细胞浸润和减弱促炎基因表达来保护心脏免受缺血再灌注。
Background-Complement consists of a complex cascade of proteins involved in innate and adaptive immunity. The cascade can be activated through 3 distinct mechanisms, designated the classical, alternative, and lectin pathways. Although complement is widely accepted as participating in the pathophysiology of ischemia-reperfusion injury, the specific role of the lectin pathway has not been addressed.Methods and Results-Monoclonal antibodies (mAbs; P7E4 and 14C3.74, IgG1 kappa isotypes) were raised against rat mannose-binding lectin (rMBL). Both mAbs recognized rMBL-A by Western analysis or surface plasmon resonance. P7E4, but not 14C3.74, exhibited a concentration-dependent inhibition of the lectin pathway, with maximal effect at 10 mug/mL. In vivo, rats were subjected to 30 minutes of left coronary artery occlusion and 4 hours of reperfusion. Complement C3 deposition was greatly attenuated in hearts pretreated with P7E4 compared with 14C3.74-treated hearts. Pretreatment with P7E4 (1 mg/kg) significantly reduced myocardial creatine kinase loss (48%), infarct size (39%), and neutrophil infiltration (47%) compared with 14C3.74-treated animals. In addition, P7E4 pretreatment significantly attenuated the expression of proinflammatory genes (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and interleukin-6) after ischemia-reperfusion.Conclusions-The lectin complement pathway is activated after myocardial ischemia-reperfusion and leads to tissue injury. Blockade of the lectin pathway with inhibitory mAbs protects the heart from ischemia-reperfusion by reducing neutrophil infiltration and attenuating proinflammatory gene expression.