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

在失血性休克合并胸部创伤的临床相关模型中，酒精和丙酮酸乙酯对急性炎症反应和肝肺器官功能障碍的调节 - 特别关注 NF-κB 触发的病理

• 批准号: 262091065
• 负责人: Professor Dr. Mario Perl
• 金额: --
• 依托单位: Klinik für Unfall-, Hand-, Plastische und Wiederherstellungschirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/262091065?language=en
• 关键词: Modulation; acute; inflammatory; response; hepato

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.

在临床过程中，继颅脑损伤和失血性休克(HS)之后，器官和/或多器官衰竭(MOF)是创伤后死亡的主要原因。胸部创伤患者发生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和胸部创伤仍然构成了一个巨大的临床挑战。这两种创伤事件，无论是单独的还是合并的，都与夸大的创伤后免疫失调有关，这可能会导致MOF。血液酒精水平(BAC)阳性的创伤患者在手术后的死亡率是对照组的2-5倍。然而，在9821名有慢性酒精滥用史的创伤患者中，有713人在临床过程中出现了较高的多器官功能衰竭和/或脓毒症发生率。在同一项研究中，BAC阳性但无慢性酒精滥用史的创伤患者在创伤后24小时死亡率显著降低。在创伤性脑损伤患者中也描述了急性酒精中毒的这些明显的积极影响，表明与急性酒精滥用相关的住院死亡率降低。其潜在的病理生理机制尚不清楚，但讨论了急性酒精中毒的免疫抑制效应。在HS模型中，急性酒精中毒合并胸部创伤的可能影响以前从未被研究过。在这里，一个临床上相关的HS和大鼠胸部创伤的双重打击模型将被用来评估下面描述的假设。与对照组相比，HS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，在临床相关的H/R模型合并胸部创伤(H/R+TXT)中，目前还没有关于亚急性或急性(2小时)酒精应用的影响的数据。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，包括使用含有丙酮酸乙酯的再灌注液进行治疗研究。丙酮酸乙酯已经在健康的人类志愿者中被测试为安全的，并且在急性炎症模型中产生的体内效应明显类似于急性酒精应用。因此，在本研究中，将评估三个假说：1.亚急性或急性酒精应用减少局部/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，最终提高H/R+TxT后的存活率。在体外急性炎症模型中，乙醇或丙酮酸乙酯可降低人肝细胞和肺上皮细胞中核因子-kappaB的活性，并调节其凋亡率。H/R+TXT后应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。