The importance of systemic cytokines in the pathogenesis of polymicrobial sepsis and dehydroepiandrosterone treatment in a rodent model
The importance of systemic cytokines in the pathogenesis of polymicrobial sepsis and dehydroepiandrosterone treatment in a rodent model
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DOI：
10.1097/01.shk.0000081408.57952.22
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发表时间：
2003-10-01
期刊：
影响因子：
3.1
通讯作者：
van Griensven, M
中科院分区：
文献类型：
--
作者：
Hildebrand, F;Pape, HC;van Griensven, M
脓毒症的发病机制在很大程度上仍未确定。已经确定的事实是，女性与较低的死亡率相关，性类固醇激素影响免疫反应。脱氢表雄酮(DHEA)似乎在脓毒症中具有保护性免疫作用。目前还不清楚脱氢表雄酮是如何影响败血症的发病机制的。因此，我们检测了DHEA对肿瘤坏死因子受体(TNF-RI-/-)和白介素6(-/-)基因敲除小鼠细胞因子水平的影响。在盲肠结扎穿孔(CLP)诱导的多菌败血症模型上，观察了脱氢表雄酮(DHEA)对动物存活率和细胞因子浓度的影响。为阐明肿瘤坏死因子-RI的作用，对肿瘤坏死因子-RI基因敲除小鼠(肿瘤坏死因子-RI-/-)进行CLP。此外，使用IL-6基因敲除小鼠(IL-6(-/-))来阐明IL-6的作用。此外，实验在没有转基因的小鼠身上进行(野生型，WT)。在该CLP模型中，DHEA的保护作用得到证实。DHEA的应用与WT动物死亡率的降低有关。此外，DHEA治疗的动物表现出全身炎症效应的减少，这是由促炎细胞因子TNF-α、IL-1β、IL-6和抗炎细胞因子IL-10确定的。在这项工作中，证明了肿瘤坏死因子-RI是CLP后生存所必需的。应用DHEA与CLP后肿瘤坏死因子-RI-/-小鼠的死亡率降低100%至50%相关。这一结果表明，DHEA的作用不依赖于肿瘤坏死因子受体。但DHEA的应用对IL-6(-/-)小鼠的死亡率无影响。提示DHEA对多菌败血症的保护作用是通过依赖IL-6实现的。脱氢表雄酮可降低全身炎症，可通过促炎细胞因子TNF-α、IL-1β、IL-6和抗炎细胞因子IL-10进行测量。IL-6可能参与了脱氢表雄酮减少败血症后并发症的作用。相反，脱氢表雄酮似乎不依赖于肿瘤坏死因子受体。因此，脱氢表雄酮可作为脓毒症免疫调节的辅助治疗。
The pathogenesis of sepsis is still undetermined to a large extent. It is an established fact that female gender is associated with a lower mortality and that sex steroid hormones influence the immunologic response. Dehydroepiandrosterone (DHEA) seems to have a protective immunologic effect in sepsis. It is still unknown in which way DHEA influences the pathogenesis of sepsis. Therefore, the effect of DHEA application on cytokine concentrations in tumor necrosis factor (TNF) receptor (TNF-RI-/-) and interleukin-6 (IL-6(-/-)) knockout mice was determined. In a model of polymicrobial sepsis induced by coecal ligation and puncture (CLP), the effect of DHEA on survival and cytokine concentrations was examined. For clarification of the role of TNF-RI, CLP was performed in TNF-RI knockout mice (TNF-RI-/-). In addition, IL-6 knockout mice (IL-6(-/-)) were used to clarify the role of IL-6. Furthermore, experiments were performed in mice that were not genetically modified (wild type, WT). The protective effect of DHEA could be confirmed in this CLP model. DHEA application was associated with a reduction in mortality in WT animals. Moreover, DHEA-treated animals demonstrated a reduction in systemic inflammatory effects, as determined by proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and the antiinflammatory cytokine IL-10. In this work, it was shown that the TNF-RI is essential for survival after CLP. DHEA application was associated with a reduction of mortality of 100% in TNF-RI-/- mice after CLP to 50%. This result engages, that the effect of DHEA is TNF-RI independent. However, the application of DHEA had no influence on the mortality in IL-6(-/-) mice. It can be concluded that the protective effect of DHEA in polymicrobial sepsis is mediated IL-6 dependently. DHEA reduces the systemic inflammation, measurable via the proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and the antiinflammatory cytokine IL-10. IL-6 might be involved in the DHEA-mediated reduction of postseptic complications. In contrast, DHEA seems to be TNF-RI independent. Consequently, DHEA might be useful as an adjunct therapy for the immune modulation in sepsis.