Immuno-metabolic dysfunction in alcohol with sepsis

摘要 酒精依赖是脓毒症死亡的独立危险因素，但其机制尚不清楚。这个 这项提案的目标是填补这一空白，并研究潜在的靶向治疗。乙醇抑制免疫功能 在脓毒症小鼠模型中的反应和增加死亡率。脓毒症每年导致超过25万名患者死亡， 这是美国最昂贵的疾病。脓毒症从早期/高炎症转化的免疫反应- 到晚期/低炎性和免疫抑制阶段；大多数脓毒症死亡发生在 炎症减退，不能清除病原体。白细胞渗出和致病前的黏附 清除，是炎症的一个速率决定因素。利用体内白细胞粘附性检测微血管 在小鼠和细胞模型中的炎症反应，我们报道了已知的抗炎药物sirtuins(SIRTs) 蛋白质，对于向低度炎症的转变至关重要。具体地说，我们报道了sirtuin 2的关键作用。 (SIRT2)在脓毒症中。SIRT2的表达在肥胖的高炎症期间减少，并在炎症减退期间被诱导 败血症小鼠。我们强有力的初步数据表明，乙醇可以诱导早期和持续的SIRT2表达， 抑制体内微血管白细胞黏附，损害细菌清除，降低脓毒症患者的存活率- 老鼠。相比之下，在SIRT2缺陷小鼠中，乙醇合并脓毒症显著改善了白细胞的黏附 反应、细菌清除和提高存活率。我们确认SIRT2偶联与p38 MAPK激活 脓毒症时IL-10在乙醇中的表达。我们还发现，SIRT2的线粒体积累是 伴有线粒体功能受损和糖酵解。我们的首要目标是研究免疫学- 合并脓毒症的乙醇代谢障碍。我们将研究乙醇引起免疫- SIRT2-p38MAPK-IL-10途径在两个互补但独立的脓毒症中的代谢障碍 具体目标： 目的1：探讨乙醇对脓毒症免疫代谢功能的影响。 目的：探讨SIRT2在酒精致脓毒症免疫代谢紊乱中的作用。 这些实验的成功完成将揭示SIRT2在免疫代谢功能障碍中的作用 饮酒和潜在导致基于SIRT2的新的治疗靶点，其广泛应用于 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.