Immuno-metabolic dysfunction in alcohol with sepsis

摘要 酒精依赖是败血症死亡的独立危险因素，但其机制尚不清楚。的 本提案的目的是填补这一空白，并研究潜在的靶向治疗。乙醇抑制免疫 在脓毒症小鼠模型中，败血症每年导致超过25万名患者死亡， 美国最昂贵的条件。脓毒症从早期/高度炎症转变的免疫应答- 晚期/低炎症和免疫抑制阶段;大多数脓毒症死亡发生在 炎症减轻，不能清除病原体。外渗前白细胞粘附与病原体 清除率是炎症的速率决定因素。白细胞粘附法检测微血管 在小鼠和细胞模型的炎症反应，我们报告，sirtuins（SIRTs），已知的抗炎 蛋白质，对于过渡到低炎症至关重要。具体来说，我们报道了sirtuin 2的关键作用， （SIRT 2）在败血症。SIRT 2表达在肥胖症患者的高炎症过程中降低，在低炎症过程中诱导。 败血症小鼠我们强有力的初步数据表明，乙醇诱导早期和持续的SIRT 2表达， 抑制体内微血管白细胞粘附，损害细菌清除并降低脓毒症患者的存活率- 小鼠相比之下，SIRT 2缺陷小鼠中脓毒症的乙醇显示出显著改善的白细胞粘附 反应，细菌清除和增加存活。我们鉴定了SIRT 2与p38 MAPK激活的偶联， 和IL-10在脓毒症的乙醇中的表达。我们还发现，SIRT 2在线粒体中的积累， 并伴有线粒体功能和糖酵解受损。我们的首要目标是研究免疫- 酒精代谢紊乱合并败血症我们将研究乙醇引起免疫- 通过SIRT 2-p38 MAPK-IL-10途径，在两个互补但独立的 具体目标： 目的1：探讨酒精对脓毒症免疫代谢功能的影响。 目的2：探讨SIRT 2在酒精性脓毒症免疫代谢紊乱中的作用。 这些实验的成功完成将为SIRT 2在免疫代谢功能障碍中的作用提供信息， 饮酒，并可能导致新的SIRT 2为基础的治疗目标，具有广泛的应用， 治疗急性/慢性炎症。

Abstract Alcohol dependence is an independent risk factor for sepsis-mortality but the mechanisms are unknown. The goal of this proposal is to fill this gap and investigate potential targeted treatment. Ethanol represses immune response and increases mortality in mouse model of sepsis. Sepsis kills over 250,000 patients annually and is the most expensive condition in the US. Immune response in sepsis transitions from early/ hyper-inflammatory- to a late/hypo-inflammatory and immunosuppressive phase; majority of the sepsis-mortality occurs during hypo-inflammation with inability to clear pathogen. Leukocyte adhesion prior to extravasation and pathogen clearance, is a rate determining factor in inflammation. Using in vivo leukocyte adhesion to test microvascular inflammatory response in mice and cell models, we reported, sirtuins (SIRTs), the known anti-inflammatory proteins, are crucial for transition to hypo-inflammation. Specifically, we reported a crucial role for sirtuin 2 (SIRT2) in sepsis. SIRT2 expression is decreased during hyper- and induced during hypo-inflammation in obese- sepsis mice. Our strong preliminary data suggests that ethanol induces early and sustained SIRT2 expression, represses microvascular leukocyte adhesion in vivo, impairs bacterial clearance and decreases survival in sepsis- mice. In contrast, ethanol with sepsis in SIRT2 deficient mice show significantly improved leukocyte adhesion response, bacterial clearance and increased survival. We identified SIRT2 coupling with p38 MAPK activation and IL-10 expression in ethanol with sepsis. We also found, mitochondrial accumulation of SIRT2 was accompanied by impaired mitochondrial function and glycolysis. Our overarching goal is to study immuno- metabolic dysfunction in ethanol with sepsis. We will study the hypothesis that ethanol causes immuno- metabolic dysfunction in sepsis via SIRT2-p38 MAPK- IL-10 pathway, in two complimentary but independent specific aims: Aim 1: To determine the effect of ethanol on immuno-metabolic function in sepsis. Aim 2: To determine the role of SIRT2 in immuno-metabolic dysfunction in ethanol with sepsis. Successful completion of these experiments will inform the role of SIRT2 in immuno-metabolic dysfunction with alcohol drinking and potentially lead to new SIRT2-based therapeutic targets with wide-ranging applications to treat acute/chronic inflammatory conditions.