Protective effects of anti-C5a in sepsis-induced thymocyte apoptosis
Protective effects of anti-C5a in sepsis-induced thymocyte apoptosis
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DOI：
10.1172/jci10793
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发表时间：
2000-11-01
影响因子：
15.9
通讯作者：
Ward, PA
中科院分区：
文献类型：
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作者：
Guo, RF;Huber-Lang, M;Ward, PA
脓毒症期间发生多器官凋亡。大鼠盲肠结扎穿刺（CLP）后，胸腺细胞以时间依赖性方式发生凋亡。根据胸腺重量、膜联蛋白 V 与胸腺细胞的结合以及胸腺细胞 DNA 梯形图测量，C5a 阻断显着减少了胸腺细胞凋亡。当通过输注纯化的眼镜蛇毒因子（CVF）在体内产生 C5a 时，胸腺细胞凋亡显着增加。在 CLP 早期阶段体内注射 CVF 时也发现了类似的结果。在诱导 CLP 12 小时后，动物中 caspase-3、-6 和 -9 的活性增加，但 caspase-1 和 -8 的活性没有增加。胞质细胞色素 c 水平增加了一倍，而线粒体水平则下降了 50%。 Western blot分析显示，CLP后胸腺细胞中Bcl-X-L（但不包括Bcl-2、BAX、Bad和Bim）的含量显着降低。脓毒症模型中的 C5a 阻断几乎完全抑制 caspase-3、-6 和 -9 激活，显着保留线粒体部分中的细胞色素 c，并恢复 Bcl-XL 表达。这些数据表明，补体的全身激活会诱导胸腺细胞的 C5a 依赖性凋亡，并且脓毒症期间 C5a 的阻断可挽救胸腺细胞免于凋亡。
Multiorgan apoptosis occurs during sepsis. Following cecal ligation and puncture (CLP) in rats, thymocytes underwent apoptosis in a time-dependent manner. C5a blockade dramatically reduced thymocyte apoptosis as measured by thymic weight, binding of annexin V to thymocytes, and laddering of thymocyte DNA. When C5a mas generated in vivo by infusion of purified cobra venom factor (CVF), thymocyte apoptosis was significantly increased. Similar results were found when CVF was injected in vivo during the early stages of CLP. In animals 12 hours after induction of CLP, there was an increase in the activities of caspase-3, -6, and -9, but not caspase-1 and -8. Cytosolic cytochrome c levels increased by twofold, whereas mitochondrial levels showed a 50% decrease. Western blot analysis revealed that the content of Bcl-X-L (but not of Bcl-2, BAX, Bad, and Bim) significantly decreased in thymocytes after CLP. C5a blockade in the sepsis model almost completely inhibited caspase-3, -6, and -9 activation, significantly preserved cytochrome c in the mitochondrial fraction, and restored Bcl-XL expression. These data suggest that systemic activation of complement induces C5a-dependent apoptosis of thymocytes and that the blockade of C5a during sepsis rescues thymocytes from apoptosis.