Multi-organ Inflammatory Responses after Burn Trauma

烧伤后多器官炎症反应

• 批准号: 9906047
• 负责人: ELIZABETH J. KOVACS
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906047
• 关键词: Accounting; Acute; Adult; Adult Respiratory Distress Syndrome; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Intoxication; Alcohols; Animal Model; Architecture; Attenuated; Bacteria; Biological Markers; Blood; Blood Circulation; Burn Trauma; Burn injury; Characteristics; Clinical; Cutaneous; Development; Disease; Distal; Endothelial Cells; Endotoxins; Enzymes; Epithelial; Epithelial Cells; Epithelium; Excess Mortality; Failure; Family; Functional disorder; Goals; Homeostasis; Hospitals; Immune System Diseases; Immune system; Impairment; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Injury; Intestinal permeability; Intestines; Intoxication; Ischemic Bowel Disease; Knowledge; Lead; Leaky Gut; Leukocyte Trafficking; Lung; Lung infections; Lymphatic; Measures; Mechanical ventilation; Mediating; Military Personnel; Minor; Monitor; Morbidity - disease rate; Mucous Membrane; Multiple Organ Failure; Mus; Myosin Light Chain Kinase; Natural Immunity; Organ; Outcome; Patients; Permeability; Play; Pneumonia; Population; Post-Traumatic Stress Disorders; Predisposition; Process; Production; Proteins; Pulmonary Edema; Pulmonary Inflammation; Recording of previous events; Respiratory Failure; Respiratory physiology; Role; Secondary to; Skin; Skin injury; Soldier; Testing; Therapeutic Intervention; Tight Junctions; Time; Tissues; Trauma; Traumatic Brain Injury; Traumatic injury; Travel; United States; Veterans; Wild Type Mouse; Work; alcohol exposure; body system; burn wound; chemokine; circulating biomarkers; clinically relevant; clinically significant; combat; commensal bacteria; cost; cytokine; cytokine release syndrome; drinking; improved; improved functioning; indexing; inhibitor/antagonist; intestinal barrier; intestinal epithelium; kinase inhibitor; leukocyte activation; lung injury; mortality; mouse model; novel therapeutic intervention; pathogen; repaired; respiratory hypoxia; response; response to injury; restoration; skin burn; stem; systemic inflammatory response; time use; tissue injury; wound care

Burn is a form of traumatic injury that affects more than just the skin and can cause damage to multiple organ systems. Of the one million people per year who suffer burn injuries in the United States, 40,000 are admitted to hospitals. Remarkably, about half of those patients are intoxicated at the time of injury. Burn patients who were intoxicated when they sustained their injuries have increased morbidity and mortality compared to burn patients 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. However, little is known about the mechanism by which alcohol intoxication modulates systemic inflammatory responses that lead to excessive pulmonary inflammation and increased susceptibility to lung infection and damage in burn victims. Evidence suggests that reduced integrity of the epithelial barrier of the gut secondary to burn injury plays a critical role in this process. Burn trauma and alcohol intoxication independently reduce the intestinal barrier integrity by altering the localization of epithelial tight junction proteins. Following the dual insult of alcohol intoxication and burn injury, the responses are compounded (additively, if not synergistically). The result is a more dramatic release of bacterial products and endotoxins into the portal and systemic circulation, triggering the so-called “cytokine storm” characteristic of injury-induced systemic inflammation. From these observations, we hypothesize that after burn injury, 1) intestinal dysfunction, including a breach in the integrity of the intestinal epithelial barrier, mediates the observed multi-organ complications, 2) that these changes can be monitored by measuring biomarkers of intestinal damage and inflammation in the blood, and that 3) gut-directed therapies will restore intestinal and systemic homeostasis improving the function of distal organs such as the lung. To test this hypothesis, first, in Aim 1, we will examine whether intestinal barrier dysregulation in the setting of alcohol intoxication and burn injury precedes pulmonary inflammation and if the intestinal barrier changes can be followed over time using a panel of blood-borne biomarkers. In Aim 2, we will investigate whether restoration of intestinal barrier integrity attenuates systemic and pulmonary indices of inflammation in our mouse model of alcohol intoxication and burn injury and whether repairing the intestinal barrier improves the pulmonary response to an infection. Lastly, in Aim 3, we will study burn patients, with and without recent alcohol intoxication, longitudinally to determine if the superimposed impact of burn injury with alcohol abuse alters intestinal barrier dysregulation to a greater extent than burn or alcohol alone. Moreover, we will see if there is a relationship between intestinal dysregulation and systemic and pulmonary inflammation. In this aim, we will also assess circulating biomarkers of inflammation and intestinal barrier damage and determine if they can be used to predict acute hypoxic respiratory failure and poor responses following pulmonary infections. Taken together, these studies will expand on the limited knowledge of how alcohol intoxication alters the gut intestinal barrier in the context of burn trauma. Studies targeting the gut in our animal model can serve as the first step in developing novel therapeutic interventions for the treatment of patients with burn injuries in active military and veteran populations. Moreover, this work has implications that extend beyond burn injury as intestinal barrier dysfunction may play a role in non-burn injury related disorders ranging from traumatic brain injury to post-traumatic stress disorder.

烧伤是一种外伤，不仅影响皮肤，还可能对多个器官造成损害 系统。美国每年有 100 万人遭受烧伤，其中 4 万人入院治疗 去医院。值得注意的是，大约一半的患者在受伤时处于醉酒状态。烧伤患者有哪些 与烧伤相比，受伤时醉酒的发病率和死亡率增加 没有饮酒的患者。肺是远程损伤后最常见的衰竭器官，例如 皮肤烧伤，45% 的烧伤患者即使在没有治疗的情况下也会出现某种形式的肺部损伤 吸入性损伤。肺炎和急性呼吸窘迫综合征（ARDS）是主要的 中毒烧伤患者中常见的并发症。然而，人们对其中的机制知之甚少 酒精中毒会调节全身炎症反应，导致肺部过度呼吸 炎症以及烧伤患者肺部感染和损伤的易感性增加。有证据表明 烧伤继发的肠道上皮屏障完整性降低在此过程中起着关键作用。 烧伤和酒精中毒通过改变肠道屏障完整性来独立降低肠道屏障的完整性。 上皮紧密连接蛋白的定位。经历了酒精中毒和烧伤的双重伤害后， 这些反应是复合的（相加的，如果不是协同的）。结果是更加戏剧化的释放 细菌产物和内毒素进入门静脉和体循环，引发所谓的“细胞因子” 损伤引起的全身炎症的“风暴”特征。根据这些观察，我们假设 烧伤后，1）肠道功能障碍，包括肠上皮完整性的破坏 屏障，介导观察到的多器官并发症，2）这些变化可以通过以下方式监测 测量血液中肠道损伤和炎症的生物标志物，以及 3) 肠道导向 治疗将恢复肠道和全身稳态，改善远端器官的功能 比如肺。为了检验这个假设，首先，在目标 1 中，我们将检查肠道屏障是否 酒精中毒和烧伤时的调节失调先于肺部炎症，并且如果 可以使用一组血源性生物标志物来跟踪肠道屏障随时间的变化。在目标 2 中，我们将 研究肠道屏障完整性的恢复是否会减弱全身和肺部指数 我们的小鼠酒精中毒和烧伤模型中的炎症以及是否修复肠道 屏障改善肺部对感染的反应。最后，在目标 3 中，我们将研究烧伤患者，以及 最近没有酒精中毒，纵向确定烧伤的叠加影响是否与 与单独烧伤或饮酒相比，酗酒对肠道屏障失调的影响更大。而且， 我们将看看肠道失调与全身和肺部疾病之间是否存在关系 炎。为此，我们还将评估炎症和肠道屏障的循环生物标志物 损害并确定它们是否可以用于预测急性缺氧性呼吸衰竭和不良反应 肺部感染后。总而言之，这些研究将扩展关于如何 酒精中毒会改变烧伤时的肠道屏障。针对我们肠道的研究 动物模型可以作为开发新的治疗干预措施的第一步 现役军人和退伍军人中烧伤的患者。此外，这项工作的意义在于 超出烧伤损伤范围，因为肠道屏障功能障碍可能在非烧伤损伤相关疾病中发挥作用 范围从创伤性脑损伤到创伤后应激障碍。