Modulation of the acute inflammatory response and the hepato-pulmonary organ dysfunction by alcohol and ethyl pyruvate in a clinically relevant model of hemorrhagic shock combined with chest trauma - with a particular interest in NF-kappaB-triggered patho

除头部损伤和失血性休克（HS）外，临床过程中的器官和/或多器官功能衰竭（MOF）是创伤后死亡的主要原因。胸外伤患者出现这些并发症的风险很高。因此，尽管在这一领域进行了高质量的研究，HS和胸部创伤仍然是一个巨大的临床挑战。这两种创伤事件，单独或联合都与创伤后免疫失调有关，这种失调可能以MOF结束。血液酒精水平（BAC）呈阳性的创伤患者在手术后死亡率高出2-5倍。然而，9821例有慢性酒精滥用史的创伤患者中有713例在其临床过程中出现较高的MOF和/或败血症发生率。在同一项研究中，BAC阳性但无慢性酒精滥用史的创伤患者创伤后24小时死亡率显著降低。急性酒精中毒对创伤性脑损伤患者也有明显的积极影响，表明急性酒精滥用降低了住院死亡率。潜在的病理生理机制尚不清楚，但对急性酒精中毒的免疫抑制作用进行了讨论。急性酒精中毒对hs模型合并胸部创伤的可能影响以前从未研究过。在这里，我们将使用临床相关的HS和大鼠胸部创伤双击模型来评估以下假设。与对照组相比，在昏迷和复苏（H/R）前的亚急性（12h）酒精应用对中毒动物具有保护作用。然而，目前尚无亚急性或急性（2h）酒精应用对临床相关H/R模型合并胸外伤（H/R+TxT）的影响的数据。因此，本研究的目的是评估这些影响以及潜在的病理生理机制，包括用含有丙酮酸乙酯的再灌注溶液进行治疗研究。丙酮酸乙酯已在健康人体志愿者中被证明是安全的，并且在急性炎症模型中具有与急性酒精应用明显相似的体内效应。因此，在本研究中，将评估三个假设：1。亚急性或急性酒精应用可减少局部/全身炎症反应以及器官特异性凋亡率，并降低功能和炎症器官参数，最终在H/R+ txt后提高生存率。乙醇或丙酮酸乙酯可降低体外急性炎症模型中人肝细胞和肺上皮细胞NF-kappaB的激活并调节其凋亡率。H/R+TxT后用丙酮酸乙酯治疗可产生免疫调节和组织保护作用，最终降低死亡率。

Next to head injury and hemorrhagic shock (HS), organ and/or multi organ failure (MOF) in the clinical course are main causes of mortality from/after trauma. Chest trauma patients are at high risk for these complications. Therefore, despite high-quality research in this field, HS and chest trauma constitute a large clinical challenge still. Both traumatic events, alone or in combination are associated with an exaggerated post-traumatic immunological dysregulation that might end in MOF.Trauma patients with positive blood alcohol levels (BAC) have 2-5fold higher mortality rates after surgical procedures. However, 713 out of 9821 trauma patients with a chronic alcohol abuse history developed higher MOF and/or sepsis rates in their clinical course. In the same study, trauma patients with positive BAC but no history of chronic alcohol abuse had significantly lower 24-h-mortality after trauma. These apparently positive effects of acute alcohol intoxication are described in patients with traumatic-brain-injury also, showing reduced in-hospital-mortality associated with acute alcohol abuse. The underlying pathophysiological mechansims are not clarified yet, but immune-suppressive effects of acute alcohol intoxication are discussed. Possible effects of acute alcohol intoxication in a HS-model combined with chest trauma have never been researched before. Here, a clinically relevant double-hit model of HS and chest trauma in rats will be used for the evaluation of below described hypothesis. Sub-acute (12h) alcohol application before HS and resuscitation (H/R) was protective for intoxicated animals compared to controls. However, there are no existing data on the effects of sub-acute or acute (2h) alcohol application in the clinically relevant H/R-model combined with chest trauma (H/R+TxT). Therefore, the aim of the present study is to evaluate these effects as well as the underlying pathophysiological mechanisms, including a therapy study with a reperfusion-solution containing ethyl pyruvate. Ethyl pyruvate has been tested as safe in healthy human volunteers, and exerts apparently similar in-vivo-effects as acute alcohol application in models of acute inflammation. Therefore, in the present study, three hypothesis will be evaluated:1. Sub-acute or acute alcohol application reduces local/systemic inflammatory reactions as well as organ-specific apoptosis rates and diminishes functional and inflammatory organ parameters ending in enhanced survival rates after H/R+TxT.2. Alcohol or ethyl pyruvate reduce NF-kappaB activation in an in vitro model of acute inflammation in human hepatocytes and lung epithelial cells and modulate their apoptosis rates.3. Therapeutic treatment with etyl pyruvate after H/R+TxT leads to immunomodulatory and tissue-protective effects ending in reduced mortality rates.