Functions of the complement components C3 and C5 during sepsis
Functions of the complement components C3 and C5 during sepsis
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DOI：
10.1096/fj.08-110595
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发表时间：
2008-10-01
期刊：
影响因子：
4.8
通讯作者：
Ward, Peter A.
中科院分区：
文献类型：
--
作者：
Flierl, Michael A.;Rittirsch, Daniel;Ward, Peter A.
补体系统的激活是脓毒症发病机制中的一个关键事件。然而，其确切机制仍未得到充分理解。在当前的研究中，我们检测了补体C3和C5在野生型以及C3或C5缺陷型小鼠盲肠结扎穿孔诱导的脓毒症中的作用。与野生型小鼠相比，C5（-/-）小鼠的存活率相同，而C3（-/-）小鼠的存活率显著降低。有趣的是，这与促炎介质血浆水平的显著降低有关。此外，尽管脓毒症C3（-/-）动物的血源性细菌增加了10倍，但与野生型小鼠相比，C5（-/-）动物的菌血症增加了400倍。这些效应与C5（-/-）小鼠无法组装末端膜攻击复合物（MAC）有关，这是通过补体溶血活性（CH - 50）测定的。令人惊讶的是，尽管阴性对照C3（-/-）小鼠无法产生MAC，但在脓毒症C3（-/-）小鼠中发现MAC形成显著增加。总之，我们的数据证实溶血补体活性对于控制脓毒症小鼠的菌血症至关重要。因此，在脓毒症期间，阻断C5a或其受体（而非C5）似乎是一种更有前景的策略，因为阻断C5a仍允许MAC形成，同时可防止C5a的不良影响。
Activation of the complement system is a key event in the pathogenesis of sepsis. Nevertheless, the exact mechanisms remain inadequately understood. In the current study, we examined the role of complement C3 and C5 in sepsis in wild-type and C3- or C5-deficient mice induced by cecal ligation and puncture. When compared to wild-type mice, C5(-/-) showed identical survival, and C3(-/-) presented significantly reduced survival. Interestingly, this was associated with significant decreases in plasma levels of proinflammatory mediators. Moreover, although septic C3(-/-) animals displayed a 10-fold increase of blood-borne bacteria, C5(-/-) animals exhibited a 400-fold increase in bacteremia when compared to wild-type mice. These effects were linked to the inability of C5(-/-) mice to assemble the terminal membrane attack complex (MAC), as determined by complement hemolytic activity (CH-50). Surprisingly, although negative control C3(-/-) mice failed to generate the MAC, significant increases of MAC formation was found in septic C3- mice. In conclusion, our data corroborate that hemolytic complement activity is essential for control of bacteremia in septic mice. Thus, during sepsis, blockade of C5a or its receptors (rather than C5) seems a more promising strategy, because C5a-blockade still allows for MAC formation while the adverse effects of C5a are prevented.