Alcohol and Burn Trauma: Multi-organ Inflammatory Responses

酒精和烧伤：多器官炎症反应

• 批准号: 10192755
• 负责人: ELIZABETH J. KOVACS
• 金额: $ 43.06万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192755
• 关键词: Address; Adult; Adult Respiratory Distress Syndrome; Alcohol consumption; Alcoholic Intoxication; Alcohols; Applications Grants; Bacteria; Biological Markers; Blood Circulation; Burn Trauma; Burn injury; Cutaneous; Development; Distal; Distant; Endotoxins; Epithelial Cells; Failure; Functional disorder; Grant; Homeostasis; Infection; Inflammation; Inflammatory Response; Inhalation; Injury; Intestinal permeability; Intestines; Knowledge; Laboratories; Lead; Lung; Lung infections; Measures; Modeling; Monitor; Morbidity - disease rate; Multiple Organ Failure; Organ; Outcome; Patients; Plasma; Pneumonia; Predisposition; Process; Pulmonary Inflammation; Recovery; Reporting; Research; Risk; Secondary to; System; Testing; Time; Trauma; alcohol effect; alcohol exposure; cell injury; clinically relevant; design; drinking; dysbiosis; fecal microbiome; gut microbiome; improved functioning; intestinal barrier; intestinal epithelium; lung injury; microbial; microbiome; mortality; mouse model; novel therapeutics; programs; response; response to injury; skin burn; stem; systemic inflammatory response

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.

项目摘要/摘要 这R35 MIRA赠款申请旨在调查负责夸大的机制 酒精中毒对烧伤后多器官系统反应的影响在每年的百万人口中 在美国遭受烧伤，将近一半的成年患者在受伤时处于醉酒状态。 与未中毒的烧伤患者相比，中毒烧伤患者的发病率和死亡率增加 喝酒肺是最常见的器官衰竭后，远程损伤，如皮肤烧伤，有45%的 烧伤患者即使没有吸入性损伤也表现出某种形式的肺损伤。肺炎和 急性呼吸窘迫综合征（ARDS）是中毒性烧伤的主要并发症之一 患者关于酒精中毒上调烧伤后全身性炎症反应的机制知之甚少。 导致肺部过度炎症和肺部易感性增加的炎症反应 感染最近，我们报道了烧伤后肺部炎症反应加剧， 中毒的受试者，因为在肠上皮屏障的完整性破坏继发于烧伤。 这一点，沿着粪便微生物组的生态失调，可能与全身性炎症密切相关 烧伤后看到的。我们和其他人已经证明，烧伤创伤和酒精中毒， 导致这些肠道变化，在酒精和烧伤的“两次打击”之后，这些反应 被放大，这可能会导致微生物组发生更大的变化并释放更多的细菌 产品和内毒素进入循环，引发全身炎症和损害远端器官 比如肺到目前为止，我们对肠道如何以及何时从远程损伤中恢复知之甚少， 作为一个皮肤烧伤，甚至更少关于如何因素，包括酒精中毒受伤前改变 这个过程。在这项研究计划中，我们将使用临床相关的酒精中毒小鼠模型， 和烧伤沿着烧伤患者，其中一些人在维持他们的生命之前会饮酒。 1）酒精中毒和烧伤的影响是什么？ 肠道，特别是肠道上皮屏障和粪便微生物组的完整性，以及 他们持续？2)肠上皮细胞屏障功能障碍能否通过测量血浆准确监测 肠上皮细胞损伤，微生物易位和炎症的生物标志物，而不是更多 侵入性测试3)是否有肠道导向疗法可以恢复肠道屏障和微生物 稳态，其通过减少全身炎症，将改善远端器官的功能， 比如肺？总之，这些研究将扩大酒精暴露如何改变 在远程损伤如烧伤的背景下， 治疗烧伤和其他形式的创伤患者。