Alcohol, GILZ and LPS Sepsis

摘要 脓毒症是世界范围内死亡的主要原因。大约250，000例败血症导致的死亡发生 每年仅在美国。尽管进行了大量的研究， 全身炎症反应综合征是不完全的。一种常见的败血症是由 革兰氏阴性菌感染引起的脂多糖（LPS）中毒。最新的基因分析显示， 小鼠的LPS抵抗揭示了糖皮质激素诱导的亮氨酸拉链（GILZ）在保护中的关键作用 抵抗LPS诱导的脓毒症我们最近发现，急性乙醇暴露上调GILZ 表达，并保护小鼠免受LPS感染性休克。此外，其他人的研究表明， 异丙醇保护小鼠免受葡萄球菌肠毒素B诱导的脓毒性休克。这些发现促使 我们试图寻找酒精激活GILZ基因和酒精衰减GILZ基因之间的潜在联系。 LPS和SEB诱导的脓毒症。总的假设是骨髓源性免疫细胞中的GILZ 是酒精对细菌毒素诱导的脓毒症的保护作用的关键， 结构上接近乙醇的醇类具有相同的免疫抑制机制。 R21应用的两个具体目标是：1）检验GILZ耗竭的假设， 骨髓来源的免疫细胞消除了乙醇对LPS和SEB诱导的脓毒性休克的保护作用; 2)为了检验结构上接近乙醇的短链醇共享 上调GILZ表达和保护免受LPS诱导的败血性休克的相同性质， SEB该项目的完成将确定GILZ是否是控制宿主免疫的关键调节剂 对细菌毒素的反应。对这一机制的分子理解将定义新的治疗方法。 更好地干预脓毒症的目标。

ABSTRACT Sepsis is a major cause of mortality worldwide. Approximately 250,000 sepsis-resulted deaths occur each year in the United States alone. In spite of vigorous research, molecular understanding of this systemic inflammatory response syndrome is not complete. A common type of sepsis results from lipopolysaccharide (LPS) intoxication from Gram-negative bacterial infection. The latest genetic analyses on LPS resistance in mice reveal the critical role of Glucocorticoid-Induced Leucine Zipper (GILZ) in protection against LPS-induced sepsis. We recently discovered that acute ethanol exposure upregulates GILZ expression, and protects mice from LPS septic shock. Moreover, research by others indicates that isopropanol protects mice from Staphylococcal enterotoxin B-induced septic shock. These findings prompt us to seek the potential link between alcohol activation of the GILZ gene and alcohol attenuation of the sepsis induced by LPS and SEB. The overall hypothesis is that GILZ in marrow-derived immune cells is pivotal to alcohol protection against sepsis induced by bacterial toxins, and the short-chain alcohols that are structurally close to ethanol share the same mechanism for immunosuppression. Two specific aims are proposed for this R21 application: 1) to test the hypothesis that GILZ depletion in marrow-derived immune cells abrogates ethanol protection against septic shock induced by LPS and SEB; 2) to examine the prediction that the short-chain alcohols which are structurally close to ethanol share the same properties of upregulating GILZ expression and protecting against septic shock induced by LPS and SEB. Completion of this project will determine whether GILZ is a key regulator controlling the host immune response to the bacterial toxins. Molecular understanding of this mechanism will define new therapeutic targets for better intervention of sepsis.