Alcohol and Burn Trauma: Multi-organ Inflammatory Responses

项目摘要/摘要 此R35 Mira拨款申请旨在调查导致夸大 酒精中毒对烧伤后多器官系统反应的影响。每年的百万人口中 在美国，近一半的成年患者在受伤时是醉酒的。 与未中毒的烧伤患者相比，中毒的烧伤患者的发病率和死亡率有所增加 喝酒。肺部是皮肤烧伤等远程损伤后最常见的衰竭器官，45%的患者 烧伤患者即使在没有吸入性损伤的情况下也会表现出某种形式的肺损伤。肺炎和 急性呼吸窘迫综合征(ARDS)是中毒烧伤的主要并发症之一。 病人。酒精中毒上调烧伤后全身系统功能的机制目前知之甚少。 导致过度肺部炎症和肺部易感性增加的炎症反应 感染。最近，我们报道了烧伤后的肺部炎症反应在 醉酒受试者由于肠道上皮屏障的完整性被破坏继发烧伤。 这与粪便微生物群的失调一起，可能是全身炎症的关键因素。 烧伤后可见。我们和其他人已经证明，烧伤创伤和酒精中毒 引起这些肠道变化，以及在酒精和烧伤的“两击”侮辱后，这些反应 被放大，这可能导致微生物组更戏剧性的变化和细菌的更大释放 产物和内毒素进入循环，引发全身炎症和对远处器官的损害 就像肺一样。到目前为止，我们对肠道如何以及何时从远程损伤中恢复知之甚少，例如 作为皮肤烫伤，关于受伤前酒精中毒等因素是如何改变的就更少了 这一过程。在这个研究项目中，我们将使用我们的临床相关的酒精中毒小鼠模型 以及烧伤患者，其中一些人在持续饮酒之前会饮酒 1)酒精中毒和烧伤对健康的影响是什么？ 肠道，特别是肠道上皮屏障和粪便微生物群的完整性，以及 它们能持续多久？2)通过测量血浆能准确监测肠上皮细胞屏障功能障碍吗？ 肠上皮细胞损伤、微生物移位和炎症的生物标志物，而不是更多 侵入性测试？3)有没有肠道导向疗法可以恢复肠道屏障和微生物 动态平衡，通过减少全身炎症，将改善远端器官的功能， 比如肺？综上所述，这些研究将扩大人们对酒精暴露如何改变健康状况的了解。 肠道在烧伤等远程损伤的情况下，并可能导致开发新的治疗方法 治疗烧伤和其他形式的创伤患者。

Project Abstract/Summary This R35 MIRA grant application is designed to investigate mechanisms responsible for the exaggerated effects of alcohol intoxication on multi-organ system responses after burn injury. Of the million people per year who suffer burn injuries in the U.S., nearly half of the adult patients are intoxicated at the time of injury. Intoxicated burn patients have increased morbidity and mortality compared to those who had not been drinking. The lung is the most frequent organ to fail after a remote injury such as cutaneous burn, with 45% of burn patients showing some form of lung damage even in the absence of inhalation injury. Pneumonia and acute respiratory distress syndrome (ARDS) are among the major complications seen in intoxicated burn patients. Little is known about the mechanism by which alcohol intoxication upregulates the post-burn systemic inflammatory responses that lead to excessive pulmonary inflammation and increased susceptibility to lung infection. Recently, we reported that the post-burn pulmonary inflammatory response is exacerbated in intoxicated subjects because of a breach in the integrity of the intestinal epithelial barrier secondary to burn. This, along with dysbiosis of the fecal microbiome, could be critically involved in the systemic inflammation seen after burn injury. We and others have shown that burn trauma and alcohol intoxication independently cause these intestinal changes and that, after the “two hit” insult of alcohol and burn injury, these responses are amplified, which could result in a more dramatic shift in the microbiome and a greater release of bacterial products and endotoxins into the circulation, triggering systemic inflammation and damage to distant organs like the lung. To date, we know very little about how and when the intestine recovers from remote injury, such as a cutaneous scald burn, and even less about how factors including alcohol intoxication prior to injury alter that process. In this research program, we will use our clinically-relevant murine model of alcohol intoxication and burn injury along with burn patients, some of whom will have consumed alcohol prior to sustaining their injuries, to address the following questions: 1) What are the effects of alcohol intoxication and burn injury on the gut, specifically, the integrity of the intestinal epithelial barrier and the fecal microbiome, and how long do they last? 2) Can intestinal epithelial cell barrier dysfunction be accurately monitored by measuring plasma biomarkers of intestinal epithelial cell damage, microbial translocation and inflammation, rather than by more invasive tests? 3) Are there gut-directed therapies that can restore the intestinal barrier and microbial homeostasis, which, by virtue of reducing systemic inflammation, will improve the function of distal organs, such as the lung? Taken together, these studies will expand the knowledge of how alcohol exposure alters the gut in the context of remote injury such as burns and may lead to the development of novel therapies for the treatment of patients with burns and other forms of trauma.