Role of acute ethanol exposure and TLR4 in early events of sepsis in a mouse model
Role of acute ethanol exposure and TLR4 in early events of sepsis in a mouse model
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DOI：
10.1016/j.alcohol.2011.07.003
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发表时间：
2011-12-01
期刊：
影响因子：
2.3
通讯作者：
Nanduri, Bindu
中科院分区：
文献类型：
--
作者：
Bhatty, Minny;Jan, Basit L.;Nanduri, Bindu
脓毒症是世界范围内的主要死亡原因。已知相关风险和死亡率在接触酒精（慢性或急性）时显著增加。急性乙醇摄入与脓毒症预后不良相关的潜在机制在很大程度上尚不清楚。本文所述的研究旨在详细确定乙醇和TLR 4在脓毒症综合征发病机制中的作用。急性乙醇暴露和TLR 4对细菌清除，脾细胞数量，腹腔巨噬细胞数量和细胞因子产生的影响进行了评估，使用野生型和TLR 4低反应小鼠用乙醇处理，然后用大肠杆菌的非致病性菌株的挑战。乙醇处理的小鼠表现出减少的细菌清除率，并产生较少量的大多数促炎细胞因子在两个品系的小鼠在2小时后的挑战。无论是乙醇处理，也没有低反应性TLR 4有显着影响的细胞数量在腹腔和脾脏感染后2小时。急性乙醇暴露对细胞因子和趋化因子产生的抑制作用在野生型小鼠中更明显，但未治疗的低反应小鼠产生的大多数细胞因子比未治疗的野生型小鼠少。本研究的主要结论是，急性乙醇暴露抑制促炎性细胞因子的产生，并且低反应性TLR 4（在C3 H/HeJ小鼠中）降低促炎性细胞因子水平，但是通过其他受体诱导的细胞因子和其他介质足以最终清除感染，但不足以诱导致死性脓毒性休克。此外，本文报道的结果证明了急性乙醇暴露对白血病抑制因子和嗜酸性粒细胞趋化因子的先前未知的影响，并提供了第一个证据表明，白细胞介素（IL）-9通过TLR 4在体内诱导。(C)2011 Elsevier Inc. All rights reserved.
Sepsis is a major cause of death worldwide. The associated risks and mortality are known to significantly increase on exposure to alcohol (chronic or acute). The underlying mechanisms of the association of acute ethanol ingestion and poor prognosis of sepsis are largely unknown. The study described here was designed to determine in detail the role of ethanol and TLR4 in the pathogenesis of the sepsis syndrome. The effects of acute ethanol exposure and TLR4 on bacterial clearance, spleen cell numbers, peritoneal macrophage numbers, and cytokine production were evaluated using wild-type and TLR4 hyporesponsive mice treated with ethanol and then challenged with a nonpathogenic strain of Escherichia coli. Ethanol-treated mice exhibited a decreased clearance of bacteria and produced lesser amounts of most pro-inflammatory cytokines in both strains of mice at 2 h after challenge. Neither ethanol treatment nor a hyporesponsive TLR4 had significant effects on the cell numbers in the peritoneal cavity and spleen 2 h postinfection. The suppressive effect of acute ethanol exposure on cytokine and chemokine production was more pronounced in the wild-type mice, but the untreated hyporesponsive mice produced less of most cytokines than untreated wild-type mice. The major conclusion of this study is that acute ethanol exposure suppresses pro-inflammatory cytokine production and that a hyporesponsive TLR4 (in C3H/HeJ mice) decreases pro-inflammatory cytokine levels, but the cytokines and other mediators induced through other receptors are sufficient to ultimately clear the infection but not enough to induce lethal septic shock. In addition, results reported here demonstrate previously unknown effects of acute ethanol exposure on leukemia inhibitory factor and eotaxin, and provide the first evidence that interleukin (IL)-9 is induced through TLR4 in vivo. (C) 2011 Elsevier Inc. All rights reserved.