Effects of a peripheral cholinesterase inhibitor on cytokine production and autonomic nervous activity in a rat model of sepsis.
Effects of a peripheral cholinesterase inhibitor on cytokine production and autonomic nervous activity in a rat model of sepsis.
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DOI：
10.1016/j.cyto.2011.11.003
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发表时间：
2012-02
期刊：
影响因子：
3.8
通讯作者：
D. Setoguchi;Henry Yatsuki;Tomohito Sadahiro;Masataka Nakamura;Y. Hirayama;Eizo Watanabe;Y. Tateishi;S. Oda
中科院分区：
文献类型：
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作者：
D. Setoguchi;Henry Yatsuki;Tomohito Sadahiro;Masataka Nakamura;Y. Hirayama;Eizo Watanabe;Y. Tateishi;S. Oda
近年来，胆碱能抗炎通路的调控被认为是控制脓毒症细胞因子产生的新策略。在脓毒症动物模型中，我们研究了是否可以通过这种途径控制高细胞分裂素血症，同时监测自主神经活动，包括心率变异性(HRV)分析的心电R-R间期。方法68只成年雄性SD大鼠(28只用于检测细胞因子的产生和自主神经活动；40只用于生存分析)。研究的每个部分涉及四个动物组，包括两个不给药的对照组。采用盲肠结扎穿刺术(CLP)建立脓毒症模型。术后90min皮下注射非选择性胆碱酯酶抑制剂溴化丁二胺(0.01 mg/kg)。连续记录CLP和假手术组动物手术前后(每隔5h)5min的心电图，进行心率变异性分析。术后20h采血检测血清细胞因子和儿茶酚胺含量。结果HRV分析显示，地塞米明能抑制CLP大鼠总功率和高频成分的减少(P<；0.05)。迪士的明显著抑制细胞因子(IL-6和IL-10)的诱导(P<；0.01)，以及血清去甲肾上腺素和多巴胺水平的升高(P<；0.05)。结论胆碱酯酶抑制剂迪士的明可抑制大鼠CLP模型中炎性细胞因子和儿茶酚胺的产生，抑制心率变异性，提示调节胆碱能抗炎途径的药物可以控制细胞因子的过量产生，参与严重脓毒症/感染性休克的发病机制。
PURPOSERecently, cholinergic anti-inflammatory pathway manipulation has been proposed as a new strategy to control cytokine production in sepsis. We investigated whether hypercytokinemia can be controlled via this pathway in an animal model of sepsis, with concomitant monitoring of autonomic nervous activity involving heart rate variability (HRV) analysis of electrocardiographic R-R intervals.METHODSSixty-eight adult male Sprague–Dawley rats were used (28 for examination of cytokine production and autonomic nervous activity; 40 for survival analysis). Each part of the study involved four animal groups, including two control groups without drug administration. Sepsis was induced by cecal ligation and puncture (CLP). Distigmine bromide, a peripheral, non-selective cholinesterase inhibitor (0.01mg/kg), was administered subcutaneously 90min after surgery. Continuous electrocardiograms were recorded for 5min before and after surgery (at intervals of 5h) in CLP and sham-operated animals for HRV analysis. Blood samples were collected 20h after surgery for serum cytokine and catecholamine assay.RESULTSOn HRV analysis, distigmine inhibited reduction of total power and high-frequency components in CLP animals (P<0.05). Distigmine significantly inhibited cytokine induction (IL-6 and IL-10) (P<0.01) as well as increase in serum levels of noradrenaline and dopamine (P<0.05). Distigmine did not significantly improve CLP animal survival rate.CONCLUSIONSThe cholinesterase inhibitor distigmine inhibited induction of inflammatory cytokines and catecholamines as well as HRV suppression in a rat CLP model, suggesting that an agent modulating the cholinergic anti-inflammatory pathway can control excess cytokine production involved in the pathogenesis of severe sepsis/septic shock.