Department of Medical Sciences, The Hedenstierna Laboratory, Uppsala University, Sweden; Department of Rheumatology and Inflammation Research, Sahlgrenska Academy, University of Gothenburg, Sweden.
J Infect. 2013 Dec;67(6):574-83. doi: 10.1016/j.jinf.2013.07.028. Epub 2013 Aug 6.
Glucocorticoid treatment in septic shock remains controversial after recent trials. We hypothesized that failure to respond to steroid therapy may be caused by decreased expression and/or function of glucocorticoid receptors (GR) and studied this in a mouse model of Staphylococcus aureus sepsis. The impact of timing of dexamethasone treatment was also investigated.
Male C57BL/6J mice were intravenously inoculated with S. aureus and GR expression and binding ability in blood, spleen and lymph nodes were analysed by means of flow cytometry. GR translocation was analysed using Image Stream. Septic mice were administered dexamethasone at 22, 26, 48, 72 and 96 h after inoculation and body weight, as a sign of dehydration, was observed.
GR expression was decreased in septic animals, but not the ligand binding capacity. GR translocation was decreased in septic mice compared to control animals. Early dexamethasone treatment (22 and 26 h) improved clinical outcome as studied by weight gain compared to when treatment was started at later time points (48, 72 and 96 h).
Our data provide evidence that GR expression is progressively decreased in experimental sepsis and that dexamethasone has a decreased ability to translocate into the cell nucleus. This may explain why steroid treatment is only beneficial when administered early in sepsis and septic shock.
最近的试验后，糖皮质激素治疗脓毒性休克仍然存在争议。我们假设对类固醇治疗无反应可能是由于糖皮质激素受体 (GR) 的表达和/或功能下降引起的，并在金黄色葡萄球菌脓毒症的小鼠模型中对此进行了研究。还研究了地塞米松治疗时机的影响。
雄性 C57BL/6J 小鼠通过静脉接种金黄色葡萄球菌，通过流式细胞术分析血液、脾脏和淋巴结中的 GR 表达和结合能力。使用图像流分析 GR 易位。接种后 22、26、48、72 和 96 小时给脓毒症小鼠给予地塞米松，并观察体重作为脱水的标志。
GR 表达在脓毒症动物中减少，但配体结合能力没有减少。与对照动物相比，GR 易位在脓毒症小鼠中减少。与在较晚时间点（48、72 和 96 小时）开始治疗相比，早期（22 和 26 小时）地塞米松治疗（通过体重增加）改善了临床结果。
我们的数据提供了证据表明，GR 表达在实验性脓毒症中逐渐下降，地塞米松向细胞核易位的能力降低。这可能解释了为什么类固醇治疗仅在脓毒症和感染性休克早期给予时才有效。
