Immunomodulatory therapies in sepsis
Immunomodulatory therapies in sepsis
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DOI：
10.1007/s001340051129
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发表时间：
2000-01-01
影响因子：
38.9
通讯作者：
Volk, HD
中科院分区：
文献类型：
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作者：
Kox, WJ;Volk, T;Volk, HD
尽管重症监护医学取得了进展，但ICU患者脓毒症的死亡率仍然很高。响应于几种感染性和非感染性刺激，单核细胞/巨噬细胞释放许多介质，包括细胞因子，其参与脓毒症的促炎反应。这些介质的过度释放导致全身炎症的发展，并在脓毒症和脓毒性休克的发病机制中起重要作用。此外，脓毒症患者还经历抗炎阶段（代偿性抗炎反应综合征），有时会出现促炎和抗炎成分的混合反应（混合拮抗反应综合征）。最初的全身性过度炎症是由炎性细胞因子的产生引起的，特别是肿瘤坏死因子-α（TNF-α），以及白细胞介素-1（IL-1）、IL-6和干扰素γ，它们在动物模型中与TNF-α协同作用诱导休克。然而，旨在使用针对内毒素、TNF-α、IL-1拮抗剂或血小板活化因子的抗体下调这些介质的临床试验已被证明是一致令人失望的。这些药物不仅没有效果，而且可能增加死亡率。这种失败的原因之一可能是在脓毒症过程中缺乏精确的免疫监测。我们最近已经证明，脓毒症显示在初始和后期阶段的双相免疫模式：早期的炎症反应相平衡的抗炎反应，这可能会导致一个hypoinflammatory状态。后者与以单核细胞失活为特征的免疫缺陷相关，即所谓的免疫麻痹。干扰素γ-1 B对代偿性抗炎反应综合征期间免疫麻痹的患者具有免疫调节作用，不仅恢复HLA-DR表达水平，而且重建单核细胞分泌细胞因子如TNF-α的能力。通过监测脓毒症患者的免疫状态，有针对性的干预可能会导致脓毒症的免疫调节更成功。
Despite advances in critical care medicine, mortality from sepsis in ICU patients remains high. In response to several infectious and non-infectious stimuli, monocytes/ macrophages release a number of mediators, including cytokines, involved in the proinflammatory response that underlies sepsis. The excessive release of these mediators results in the development of whole body inflammation, and plays an important role in the pathogenesis of sepsis and septic shock. In addition, patients with sepsis also under-go an anti-inflammatory phase (the compensatory anti-inflammatory response syndrome) and at times, a mixed response with both pro-and anti-inflammatory components (the mixed antagonistic response syndrome). The initial systemic hyper-inflammation is caused by production of inflammatory cytokines, especially tumour necrosis factor-alpha (TNF-alpha), and also interleukin-1 (IL-1), IL-6, and interferon gamma, which act synergistically with TNF-alpha in inducing shock in animal models. However, clinical trials aimed at downregulating these mediators using antibodies against endotoxin, TNF-alpha, antagonists of IL-1 or platelet activating factor have proved to be uniformly disappointing. Not only have these agents been found to have no effect, but they may also increase mortality. One of the reasons for such failure may be the lack of precise immunological monitoring during the course of sepsis. We have recently demonstrated that sepsis shows a biphasic immunological pattern during the initial and later phase: the early hyperinflammatory phase is counterbalanced by an anti-inflammatory response which may lead to a hypoinflammatory state. The latter is associated with immunodeficiency that is characterised by monocytic deactivation, so-called immunoparalysis. Interferon gamma-1 b has an immunoregulatory effect in patients with immunoparalysis during the compensatory anti-inflammatory response syndrome, not only restoring levels of HLA-DR expression but also re-establishing the ability of monocytes to secrete cytokines such as TNF-alpha. By monitoring immune status in septic patients, targeted intervention may lead to more success in immunomodulation of sepsis.