Microvascular effects of complement blockade with soluble recombinant CR1 on ischemia/reperfusion injury of skeletal muscle.
Microvascular effects of complement blockade with soluble recombinant CR1 on ischemia/reperfusion injury of skeletal muscle.
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DOI：
10.4049/jimmunol.150.11.5104
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发表时间：
1993-06
影响因子：
4.4
通讯作者：
M. Pemberton;G. Anderson;V. Vetvicka;D. Justus;G. D. Ross
中科院分区：
文献类型：
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作者：
M. Pemberton;G. Anderson;V. Vetvicka;D. Justus;G. D. Ross
缺血组织的再灌注与组织损伤有关，其程度大于单纯缺血引起的损伤。假设C激活通过膜攻击和C5 α依赖性的中性粒细胞通过C3受体募集到内皮上的C3固定位点来介导所谓的缺血/再灌注损伤。中性粒细胞的粘附是表达其有害作用的先决条件，这是缺血/再灌注损伤的病理生理学的核心。本研究旨在评估使用可溶性和截短的重组人CR 1（sCR 1）分子抑制C激活对缺血/再灌注损伤的影响，sCR 1分子是膜C3 b/C4 b受体（CD 35）的“无尾”形式，其功能是C激活的调节剂。在小鼠提睾肌模型中，再灌注后测量毛细血管灌注和白细胞粘附到微静脉内皮，该模型允许显微镜视频观察微循环变化。静脉输注sCR 1前4小时的缺血期和3小时的再灌注期防止白细胞粘附到微静脉内皮细胞的增加，在对照组中看到，并增加了55%的再灌注毛细血管的数量。台盼蓝染色显示，与对照组相比，接受sCR 1的小鼠的肌细胞活力从11%增加至50%。输注sCR 1的小鼠血液样本的试验表明，小鼠C激活旁路途径几乎完全抑制，但小鼠C激活经典途径未检测到损失。得出的结论是，在骨骼肌损伤的这种模型中的C激活可能是由于替代途径，并且在再灌注过程中抑制C激活抑制白细胞粘附到血管壁并保护毛细血管微循环。
Reperfusion of ischemic tissue is associated with tissue injury greater than that resulting from ischemia alone. C activation has been hypothesized to mediate the so-called ischemia/reperfusion injury through both membrane attack and C5a-dependent recruitment of neutrophils to sites of C3 fixation on the endothelium via C3 receptors. Adherence of neutrophils is preconditional to expression of their deleterious effects, which are central to the pathophysiology of ischemia/reperfusion injury. This study was designed to evaluate the effect of inhibition of C activation on ischemia/reperfusion injury using a soluble and truncated recombinant human CR1 (sCR1) molecule, a "tail-less" form of the membrane C3b/C4b receptor (CD35) that functions as a regulator of C activation. Capillary perfusion and leukocyte adherence to venular endothelium were measured after reperfusion in a mouse cremaster muscle model that allowed microscopic video observation of microcirculatory changes. Infusion i.v. with sCR1 before a 4-h period of ischemia and during a 3-h subsequent period of reperfusion prevented the increase in leukocyte adherence to venular endothelium seen in controls, and enhanced the number of reperfusing capillaries by 55%. Trypan blue staining showed an increase in muscle cell viability from 11 to 50% in mice receiving sCR1 as compared to controls. Tests of blood samples from mice infused with sCR1 demonstrated nearly complete inhibition of the mouse alternative pathway of C activation, but no detectable loss of the mouse classical pathway of C activation. It was concluded that C activation in this model of skeletal muscle injury is likely to be due to the alternative pathway, and that inhibition of C activation during reperfusion inhibits leukocyte adherence to blood vessel walls and protects the capillary microcirculation.