Stratification is the key: inflammatory biomarkers accurately direct immunomodulatory therapy in experimental sepsis.
Stratification is the key: inflammatory biomarkers accurately direct immunomodulatory therapy in experimental sepsis.
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DOI：
10.1097/ccm.0b013e31819df06b
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发表时间：
2009-05
影响因子：
8.8
通讯作者：
Remick DG
中科院分区：
文献类型：
--
作者：
Osuchowski MF;Connett J;Welch K;Granger J;Remick DG
本研究检查了前瞻性分层的有效性，以确定和靶向高剂量糖皮质激素治疗的受试者发展致命败血症。前瞻性、随机、实验室对照实验。大学研究实验室。成年雌性远系杂交CD-1小鼠。小鼠（n = 88）经受通过盲肠结扎和穿孔（CLP）诱导的脓毒症。根据CLP后6小时获得的白细胞介素（IL）-6血浆水平，将小鼠前瞻性分为两组，预测死亡（P-DIE）或预测存活（P-LIVE）。分层后，将地塞米松（DEX，2.5 mg/kg，两次给药）给予每组中一半的动物，而另一半接受生理盐水。如果没有分层，DEX不会带来任何好处。在P-DIE组中，盐水处理的小鼠无一存活，而DEX处理的小鼠有40%存活。与盐水处理的小鼠相比，在未存活的小鼠中，67%的死亡延迟了24 - 48小时。CLP后24小时，无论给药状态如何，P-DIE小鼠的淋巴细胞计数均高于P-LIVE小鼠，而中性粒细胞的趋势相反。盐水处理的动物中的血浆细胞因子和细胞因子抑制剂水平显示P-DIE组中的水平高于P-LIVE组中的水平（例如，IL-6为60对10 ng/mL，IL-1受体拮抗剂为453对129 ng/mL）。有趣的是，在P-DIE或P-LIVE组中，DEX治疗没有减少CLP后24小时的循环细胞因子。CLP诱导脓毒症后，早期和准确的生存预测允许靶向免疫抑制，提高生存。在没有抑制典型的促炎介质的情况下发生了更好的存活，这表明死亡不是由过量的尼古丁驱动的炎症介导的。对更严格定义的队列给予非特异性抗炎/免疫抑制治疗可能比不加区别地使用介体特异性药物更成功。
This study examined the effectiveness of prospective stratification to identify and target high-dose glucocorticoid therapy for subjects developing lethal sepsis. Prospective, randomized, laboratory-controlled experiment. University research laboratory. Adult female outbred CD-1 mice. Mice (n = 88) were subjected to sepsis induced by cecal ligation and puncture (CLP). Mice were prospectively divided into two groups, predicted to die (P-DIE) or predicted to live (P-LIVE), based on plasma levels of interleukin (IL)-6 obtained 6 hours after CLP. Following stratification, dexamethasone (DEX, 2.5 mg/kg, two doses) was administered to half the animals in each group whereas the other half received saline. Without stratification, DEX conferred no benefit. In the P-DIE group, none of saline-treated mice lived whereas 40% of the DEX-treated mice survived. Of the nonsurvivors, 67% had death delayed by 24 – 48 hours compared with saline-treated mice. Twenty-four hours post-CLP, the lymphocyte count was higher in the P-DIE than in the P-LIVE mice regardless of treatment status, whereas the opposite trend was noted for neutrophils. Plasma cytokine and cytokine inhibitor levels in the saline-treated animals showed that levels in the P-DIE group were higher than those in the P-LIVE group (e.g., 60 vs. 10 ng/mL for IL-6 and 453 vs.129 ng/mL for IL-1 receptor antagonist). Interestingly, DEX therapy did not decrease 24 hours post-CLP circulating cytokines in either the P-DIE or the P-LIVE group. Following CLP-induced sepsis, early and accurate survival prediction allows targeted immunosuppression that improves survival. Better survival occurred without suppression of the typical proinflammatory mediators, suggesting that the deaths were not mediated by excessive cytokine-driven inflammation. Nonspecific anti-inflammatory/immunosuppressive treatment administered to more rigorously defined cohorts may be more successful than mediator-specific drugs used indiscriminately.