Kox W J, Volk T, Kox S N, Volk H D
Department of Anesthesiology and Intensive Care, Humboldt University Berlin, Germany.
Intensive Care Med. 2000;26 Suppl 1:S124-8. doi: 10.1007/s001340051129.
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 undergo 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 hyperinflammation is caused by production of inflammatory cytokines, especially tumour necrosis factor-a (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 reestablishing 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.
尽管重症监护医学取得了进展，但重症监护病房（ICU）患者因败血症导致的死亡率仍然很高。针对多种感染性和非感染性刺激，单核细胞/巨噬细胞会释放多种介质，包括参与败血症潜在促炎反应的细胞因子。这些介质的过度释放会导致全身炎症的发展，并在败血症和感染性休克的发病机制中发挥重要作用。此外，败血症患者还会经历抗炎阶段（代偿性抗炎反应综合征），有时还会出现促炎和抗炎成分并存的混合反应（混合拮抗反应综合征）。最初的全身炎症是由炎性细胞因子的产生引起的，尤其是肿瘤坏死因子-α（TNF-α），还有白细胞介素-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，旨在使用抗内毒素、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均令人失望。这些药物不仅被发现无效，而且还可能增加死亡率。这种失败的原因之一可能是败血症病程中缺乏精确的免疫监测。我们最近证明，败血症在初始阶段和后期呈现双相免疫模式：早期的促炎阶段会被抗炎反应所平衡，这可能导致炎症减退状态。后者与以单核细胞失活为特征的免疫缺陷有关，即所谓的免疫麻痹。γ-1b干扰素对代偿性抗炎反应综合征期间出现免疫麻痹的患者具有免疫调节作用，不仅能恢复HLA-DR表达水平，还能重建单核细胞分泌TNF-α等细胞因子的能力。通过监测脓毒症患者的免疫状态，有针对性的干预可能会在败血症的免疫调节方面取得更大成功。
