Alcohol and Burn Trauma: Multi-organ Inflammatory Responses

酒精和烧伤：多器官炎症反应

• 批准号: 10021015
• 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/10021015
• 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; 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 此R35 MIRA赠款应用程序旨在调查负责夸张的机制 酒精肠毒性对烧伤后多器官系统反应的影响。每年有百万人 在美国遭受烧伤受伤的人，在受伤时，几乎一半的成年患者被陶醉。 与从未有过的醉酒患者相比 喝。肺是最常见的器官在远程受伤（例如皮肤烧伤）后失败的器官，其中45％ 即使在没有吸入损伤的情况下，烧伤患者即使在没有吸入损伤的情况下显示出某种形式的肺部损伤。肺炎和 急性呼吸窘迫综合征（ARDS）是陶醉的主要并发症之一 患者。关于酒精中毒会上调燃烧后系统性的机制知之甚少 导致过量肺部感染并增加肺的易感性反应 感染。最近，我们报道说，燃烧后的肺部炎症反应在 在燃烧继发的肠上皮屏障的完整性方面遭到侵犯，被介绍的受试者。 这以及粪便微生物组的营养不良，可能与全身性炎症有关 看到烧伤后。我们和其他人表明，燃烧创伤和酗酒独立 引起这些肠道变化，并在酒精和烧伤受伤的“两击”伤害后，这些反应 被放大，这可能导致微生物组的更大变化和细菌的释放更大 产物和内毒素进入循环，触发全身感染和对远处器官的损害 像肺。迄今 作为皮肤的烫伤燃烧，甚至更少关于因素如何在受伤之前包括酒精毒性改变 那个过程。在该研究计划中，我们将使用与临床上的酒精醉酒模型 并与烧伤的患者一起烧伤，其中一些人会在维持他们之前喝酒 伤害，以解决以下问题：1）酒精中毒和烧伤受伤对 肠道，特别是肠上皮屏障和粪便微生物组的完整性，以及多长时间 他们持续吗？ 2）可以通过测量血浆来准确监测肠上皮细胞屏障功能障碍 肠上皮细胞损伤，微生物易位和注射的生物标志物，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壁和微生物 体内平衡，通过减少系统性注入，可以改善远端器官的功能 例如肺部？综上所述，这些研究将扩大有关酒精暴露如何改变的知识 肠道在远程伤害的背景下，例如烧伤，可能导致开发新的疗法 治疗烧伤和其他形式的创伤患者。