From the Division of Trauma, Critical Care & Emergency Surgery, Department of Surgery, University of Arizona, Tucson, Arizona.
J Trauma Acute Care Surg. 2014 Feb;76(2):320-7; discussion 327-8. doi: 10.1097/TA.0000000000000113.
Although previous studies have described potential benefits of nonselective β-adrenergic antagonist therapy in sepsis, there is a paucity of data on the use of β1-selective antagonists (B1AA). The purposes of this study were to describe the effects of B1AA on survival in septic animals and to explore for molecular mechanisms of potential treatment benefit.
C57BL/6 male mice received intraperitoneal injection of lipopolysaccharide. Continuous infusion of a B1AA (esmolol) or an equal volume of saline (control) was initiated at 4 hours after injection. Kaplan-Meier survival analysis at 120 hours was used to explore for mortality differences. A subgroup of animals was sacrificed for microarray expression analysis. Top candidate genes were validated in vitro and in silico. Expression of our candidate genes in a human microarray database (GSE28750) was explored.
B1AA infusion resulted in increased survival (p = 0.001) at 120 hours. Mean survival difference was 23.6 hours (p = 0.002). Hazard ratio for mortality with B1AA is 0.43 (95% confidence interval, 0.26-0.72). Immunologic disease (p = 0.0003-0.036) and cell death/survival (p = 0.0001-0.042) were significantly associated with improved survival in septic mice treated with B1AA. Further analysis of the gene structure revealed that eight genes shared common promoter activating sequence for NFKB and/or BRCA1 motifs. Analysis of a human sepsis database identified the up-regulation of CAMP (p = 0.032) and TNFSF10 (p = 0.001) genes in septic patients compared with healthy controls.
Continuous infusion of a B1AA initiated after septic insult improves survival at 5 days in a murine model. Benefits may be caused by modulation of gene expression in immunologic pathways leading to an increase in CAMP and TNFSF10 expression. This observed effect may be explained by the activation of NFKB and BRCA1 genes involved in immune response and cell repair pathways. Our findings support further investigation of the use of B1AA in the treatment of sepsis.
尽管先前的研究已经描述了非选择性β肾上腺素能拮抗剂治疗败血症的潜在益处，但关于β1 选择性拮抗剂（B1AA）的使用数据却很少。本研究的目的是描述 B1AA 对败血症动物生存的影响，并探讨潜在治疗益处的分子机制。
C57BL/6 雄性小鼠接受腹腔注射脂多糖。在注射后 4 小时开始连续输注 B1AA（艾司洛尔）或等量生理盐水（对照）。使用 120 小时的 Kaplan-Meier 生存分析来探讨死亡率差异。一组动物被处死进行微阵列表达分析。在体外和在计算机上验证了顶级候选基因。在人类微阵列数据库（GSE28750）中探索了我们候选基因的表达。
B1AA 输注导致 120 小时时存活率增加（p = 0.001）。平均生存差异为 23.6 小时（p = 0.002）。B1AA 死亡率的危险比为 0.43（95%置信区间，0.26-0.72）。免疫疾病（p = 0.0003-0.036）和细胞死亡/存活（p = 0.0001-0.042）与接受 B1AA 治疗的败血症小鼠的生存改善显著相关。对基因结构的进一步分析表明，八个基因共享 NFKB 和/或 BRCA1 基序的共同启动子激活序列。对人类败血症数据库的分析表明，与健康对照相比，败血症患者的 CAMP（p = 0.032）和 TNFSF10（p = 0.001）基因上调。
在败血症模型中，在感染后开始连续输注 B1AA 可提高 5 天的生存率。益处可能是通过免疫途径的基因表达调节引起的，导致 CAMP 和 TNFSF10 表达增加。这种观察到的效应可以通过参与免疫反应和细胞修复途径的 NFKB 和 BRCA1 基因的激活来解释。我们的发现支持进一步研究 B1AA 在败血症治疗中的应用。
