Hypothesis: Combined Inhibition of Complement and CD14 as Treatment Regimen to Attenuate the Inflammatory Response
Hypothesis: Combined Inhibition of Complement and CD14 as Treatment Regimen to Attenuate the Inflammatory Response
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DOI：
10.1007/978-0-387-78952-1_18
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发表时间：
2008-01-01
期刊：
影响因子：
--
通讯作者：
Espevik, Terje
中科院分区：
文献类型：
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作者：
Mollnes, Tom Eirik;Christiansen, Dorte;Espevik, Terje
模式识别是先天免疫中的一个重要事件。补体和Toll样受体(TLR)，包括CD14分子，是天然免疫系统的两个重要上游成分，识别外源性结构和内源性配体。它们在炎症网络中部分独立发挥作用，但也有16种目前正在调查的串扰机制。补体是保护宿主免受感染的先天免疫的重要组成部分。然而，这是一把双刃剑，因为不适当的激活可能会损害宿主。在严重的败血症中，补体的不受控制的全身性激活可能导致体内平衡机制的崩溃，导致败血症休克的不可逆转状态。补体抑制对实验性致死性脓毒症有很好的保护作用，但缺乏临床研究。脂多糖(LPS)通过与CD14和TLR4/MD-2复合体结合，诱导促炎细胞因子的合成，参与革兰氏阴性脓毒症的发病机制。在动物实验中，中和内毒素或阻断CD14在预防内毒素诱导的致死性休克方面是有效的，但临床研究的结果令人失望，就像大多数其他治疗策略一样。根据最近发表的一些数据和我们实验室获得的进一步的先导数据，我们假设，抑制补体和中和CD14可能会减轻导致脓毒症时体内平衡破坏的失控炎症反应。我们进一步假设这种疗法是一种有效地抑制最初的内源性和外源性先天识别的方法，以防止炎症反应的下游激活。
Pattern recognition is an essential event in innate immunity. Complement and Toll-like receptors (TLR), including the CD14 molecule, are two important upstream components of the innate immune system, recognizing exogenous structures as well as endogenous ligands. They act partly independent in the inflammatory network, but also have 16 several cross-talk mechanisms which are under current investigation. Complement is an essential part of innate immunity protecting the host against infection. However, it is a double-edged sword since inappropriate activation may damage the host. Uncontrolled systemic activation of complement, as seen in severe sepsis, may contribute to the breakdown of homeostatic mechanisms leading to the irreversible state of septic shock. Complement inhibition is promising for protection of lethal experimental sepsis, but clinical studies are missing. Lipopolysaccharide (LPS) has been implicated in the pathogenesis of gram-negative sepsis by inducing synthesis of pro-inflammatory cytokines through binding to CD14 and the TLR4/MD-2 complex. Neutralization of LPS or blocking of CD14 has been effective in preventing LPS-induced lethal shock in animal studies, but results from clinical studies have been disappointing, as for most other therapeutic strategies. Based on some recently published data and further pilot data obtained in our laboratory, we hypothesize that inhibition of complement combined with neutralization of CD 14 may attenuate the uncontrolled inflammatory reaction which leads to breakdown of homeostasis during sepsis. We further postulate this regimen as an approach for efficient inhibition of the initial innate recognition, exogenous as well as endogenous, to prevent downstream activation of the inflammatory reaction in general.