Alcohol, GILZ and LPS Sepsis

摘要 脓毒症是世界范围内死亡的主要原因。约有250,000人死于脓毒症 每年仅在美国。尽管有大量的研究，但对这一点的分子理解 全身性炎症反应综合征并不完全。一种常见的脓毒症是由 革兰氏阴性杆菌感染所致的脂多糖中毒。最新的遗传分析 小鼠脂多糖抵抗揭示糖皮质激素诱导的亮氨酸拉链(GILZ)在保护中的关键作用 对抗脂多糖诱导的败血症。我们最近发现，急性酒精暴露会上调GILZ 表达，并保护小鼠免受内毒素感染性休克。此外，其他人的研究表明， 异丙醇对葡萄球菌肠毒素B诱导的败血症休克小鼠的保护作用。这些发现促使人们 美国寻求酒精激活GILZ基因和酒精衰减之间的潜在联系 脂多糖和SEB诱导的脓毒症。总体假设是骨髓源性免疫细胞中的GILZ 是预防细菌毒素引起的脓毒症的关键，而短链 结构上与乙醇相近的酒精具有相同的免疫抑制机制。 对于R21的应用提出了两个特定的目标：1)检验GILZ在 骨髓来源的免疫细胞取消乙醇对内毒素和SEB诱导的感染性休克的保护作用； 2)检验结构上与乙醇接近的短链醇类共享 上调GILZ表达和保护内毒素诱导的感染性休克的相同特性 塞布。该项目的完成将决定GILZ是否是控制宿主免疫的关键调节因子 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.