Ethyl Pyruvate: A Novel Treatment for Sepsis

描述（由申请人提供）： 丙酮酸乙酯（EP）是由丙酮酸和乙醇形成的酯。在初步研究中，我们已经证明，EP改善肠道和肝脏损伤或提高生存率时，它被用作治疗剂，以治疗啮齿动物遭受肠系膜缺血和再灌注，出血性休克，内毒素血症，或多微生物细菌败血症。此外，我们已经证明EP是活性氧（ROS）的有效清除剂，并且我们已经证明该化合物也是抑制促炎信号传导因子NF-κ B和p38丝裂原活化蛋白激酶活化的抗炎剂。EP还抑制一种新型细胞因子高迁移率族蛋白1（HMGB 1）的释放。通过这些令人兴奋的观察，我们建议进行一系列旨在更好地阐明EP抗炎和治疗作用机制的实验。这项工作将在三个具体目标下进行。目的1是测试可能解释EP有益作用的三个广泛假设。这些假说是：活性氧假说，烷基化假说和谷胱甘肽（GSH）耗尽假说。ROS假说认为EP作为抗氧化剂发挥作用的能力是其细胞保护和抗炎作用的原因。烷基化假说提出EP作为亲电试剂起作用，其烷基化关键硫醇基团，从而使重要的信号传导或效应分子失活，例如转录因子NF-κ B的亚基或参与细胞凋亡过程的各种半胱天冬酶。GSH耗竭假说是烷基化假说的一个变体，提出EP使GSH烷基化。GSH的消耗以有利于与NF-κ B亚基形成混合二硫化物的方式改变细胞氧化还原平衡，从而干扰通过该途径的信号传导。目的二是研究EP对NF-κ B活化的影响。目的3探讨EP抑制HMGB 1释放的机制.所有这些目标将使用分子和药理学方法的组合来实现，并且研究将采用体外（细胞培养）和体内（动物模型）方法。更好地理解负责EP的抗炎和治疗作用的机制可能允许识别参与先天免疫应答的新细胞途径。

DESCRIPTION (provided by applicant): Ethyl pyruvate (EP) is the ester formed from pyruvic acid and ethanol. In preliminary studies, we have documented that EP ameliorates intestinal and hepatic injury or improves survival when it is used as a therapeutic agent to treat rodents subjected to mesenteric ischemia and reperfusion, hemorrhagic shock, endotoxemia, or polymicrobial bacterial sepsis. In addition, we have demonstrated that EP is an effective scavenger of reactive oxygen species (ROS), and we have shown that this compound is also an anti-inflammatory agent that inhibits activation of the pro-inflammatory signaling factors, NF-KappaB and p38 mitogen-activated protein kinase. EP also inhibits release of a novel cytokine, high mobility group box 1 (HMGB1). Prompted by these exciting observations, we propose to carry out a series of experiments that are designed to better elucidate the mechanism(s) responsible for the anti-inflammatory and therapeutic effects of EP. The work will be organized under three Specific Aims. Aim 1 is to test three broad hypotheses that might account for the beneficial effects of EP. These hypotheses are: the ROS Hypothesis, the Alkylation Hypothesis, and the Glutathione (GSH) Depletion Hypothesis. The ROS Hypothesis proposes that EP's ability to function as an antioxidant accounts for its cytoprotective and anti-inflammatory effects. The Alkylation Hypothesis proposes that EP functions as an electrophile that alkylates key thiol groups and thereby inactivates important signaling or effector molecules, such as subunits of the transcription factor, NF-KappaB, or various caspases involved in the process of apoptosis. The GSH Depletion Hypothesis, a variant of the Alkylation Hypothesis, proposes that EP alkylates GSH. Depletion of GSH shifts the cellular redox balance in a way that favors the formation of mixed disulfides with NF-KappaB subunits and thereby interferes with signaling via this pathway. Aim 2 is to carry out more detailed studies on the effects of EP on NF-KappaB activation. Aim 3 is to investigate the mechanisms responsible for inhibition of HMGB 1 release by EP. All of these aims will be carried out using a combination of molecular and pharmacological approaches and the studies will employ both in vitro (cell culture) and in vivo (animal model) approaches. Achieving a better understanding of the mechanisms responsible for the anti-inflammatory and therapeutic effects of EP may permit identification of novel cellular pathways involved in the innate immune response.