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

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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.