Septic serum induces glucocorticoid resistance and modifies the expression of glucocorticoid isoforms receptors: a prospective cohort study and in vitro experimental assay
Septic serum induces glucocorticoid resistance and modifies the expression of glucocorticoid isoforms receptors: a prospective cohort study and in vitro experimental assay
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DOI：
10.1186/cc12774
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发表时间：
2013-01-01
期刊：
影响因子：
15.1
通讯作者：
Annelise Goecke, Irmgadt
中科院分区：
文献类型：
--
作者：
Guerrero, Julia;Gatica, Hector A.;Annelise Goecke, Irmgadt
背景：几十年前，糖皮质激素治疗在脓毒症动物模型中显示出保护作用。在人类脓毒症中，有新的兴趣在生理剂量的糖皮质激素治疗后，改善反应血管加压药和降低死亡率的报告，在选定的一组患者。然而，其他报告没有证实这些结果。细胞糖皮质激素抵抗可能解释了一个可能的原因。为了评估这一假设，我们评估了糖皮质激素受体β的表达，糖皮质激素受体的显性阴性亚型，在脓毒症患者的外周血单个核细胞和血清脓毒症患者的糖皮质激素受体表达和糖皮质激素敏感性的免疫cells culture.Methods的影响：一个前瞻性队列研究和体外实验研究与匹配的对照。前瞻性入组了9例感染性休克患者和9例健康对照。单核细胞和血清样品在进入重症监护室时和出院当天从脓毒症患者以及从与患者年龄和性别匹配的健康志愿者获得。通过蛋白质印迹法研究了来自患者和在脓毒症患者血清存在下培养的免疫细胞系的糖皮质激素受体α和β表达。糖皮质激素的敏感性进行了研究，在正常或脓毒症患者的血清存在下培养的对照单核细胞。采用Mann-Whitney检验进行非参数数据的统计学分析，方差分析进行多重比较; P < 0.05被认为是significant.Results：患者的糖皮质激素受体β表达在入院时显著高于出院时，而α受体没有显著差异。在体外，脓毒症血清诱导培养的T和B细胞中两种受体的表达增加，对受体β的影响大于对照血清。结论：脓毒症患者外周血单个核细胞中糖皮质激素受体β的表达短暂增加。脓毒症患者血清体外诱导细胞糖皮质激素抵抗。我们的研究结果支持脓毒症中可能存在细胞糖皮质激素抵抗。
Background: A protective role for glucocorticoid therapy in animal models of sepsis was shown many decades ago. In human sepsis, there is new interest in glucocorticoid therapy at a physiological dose after reports of improved response to vasopressor drugs and decreased mortality in a selected group of patients. However, other reports have not confirmed these results. Cellular glucocorticoid resistance could explain a possible cause of that. To evaluate this hypothesis, we evaluated the expression of glucocorticoid receptor beta, the dominant negative isoform of glucocorticoid receptor, in peripheral mononuclear cells of septic patients and the effect of serum septic patients over glucocorticoid receptor expression and glucocorticoid sensitivity in immune cells culture.Methods: A prospective cohort study and an in vitro experimental study with matched controls were developed. Nine patients with septic shock and nine healthy controls were prospectively enrolled. Mononuclear cells and serum samples were obtained from the patients with sepsis on admission to the Intensive Care Unit and on the day of discharge from hospital, and from healthy volunteers matched by age and sex with the patients. Glucocorticoid receptor alpha and beta expression from patients and from immune cell lines cultured in the presence of serum from septic patients were studied by western blot. Glucocorticoid sensitivity was studied in control mononuclear cells cultured in the presence of serum from normal or septic patients. A statistical analysis was performed using a Mann-Whitney test for non-parametric data and analysis of variance for multiple comparison; P < 0.05 was considered significant.Results: The patients' glucocorticoid receptor beta expression was significantly higher on admission than on discharge, whereas the alpha receptor was not significantly different. In vitro, septic serum induced increased expression of both receptors in T and B cells in culture, with a greater effect on receptor beta than the control serum. Septic serum induced glucocorticoid resistance in control mononuclear cells.Conclusion: There is a transient increased expression of glucocorticoid receptor beta in mononuclear cells from septic patients. Serum from septic patients induces cell glucocorticoid resistance in vitro. Our findings support a possible cell glucocorticoid resistance in sepsis.