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.

烧伤是一种创伤性损伤的一种形式，不仅影响皮肤，并可能对多器官造成伤害 系统。在美国每年遭受烧伤的100万人中，有40,000人被录取 去医院。值得注意的是，在受伤时，约有一半的患者陶醉。燃烧患者 与燃烧相比 没有喝酒的患者。肺是远程受伤后最常见的器官，例如 皮肤烧伤，有45％的烧伤患者显示出某种形式的肺损伤 吸入损伤。肺炎和急性呼吸窘迫综合征（ARDS）是主要的 醉酒患者中看到的并发症。但是，关于这种机制知之甚少 酒精肠毒性调节全身性炎症反应，导致过量肺部 炎症和对肺部感染的易感性增加和烧伤受害者的损害。有证据表明这一点 继发肠损伤的肠道上皮屏障的完整性降低在此过程中起着至关重要的作用。 烧伤创伤和酒精中毒可以独立降低肠道屏障完整性 上皮紧密连接蛋白的定位。在酒精中毒和烧伤受伤双重伤害之后， 响应复合（即使不是协同作用）。结果是更具戏剧性的版本 细菌产物和内毒素进入门户和全身循环，触发所谓的“细胞因子 风暴”的特征是受伤引起的全身注射。从这些观察结果中，我们假设 烧伤后，1）肠道功能障碍，包括肠上皮的完整性 障碍，介导观察到的多器官并发症，2）可以通过 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 疗法将恢复肠道和全身稳态，以改善远端器官的功能 例如肺。为了检验这一假设，首先，在AIM 1中，我们将检查肠屏障是否是否 在酒精毒化和烧伤损伤的情况下，失调之前是肺注射，如果 可以使用一组血源性生物标志物随着时间的推移遵循肠道屏障的变化。在AIM 2中，我们将 研究肠道屏障完整性的恢复是否会减弱 在我们的小鼠酒精醉酒和烧伤损伤的模型中炎症以及是否修复肠道 屏障改善了对感染的肺反应。最后，在AIM 3中，我们将研究烧伤患者，与 没有最近的酗酒中毒，纵向确定 酒精滥用比单独燃烧或饮酒更大程度地改变了肠道屏障的失调。而且， 我们将看看肠失调与全身和肺部之间是否存在关系 在此目标中，我们还将评估炎症和肠屏障的循环生物标志物 损坏并确定它们是否可以用于预测急性低氧呼吸衰竭和反应不佳 肺部感染后。综上所述，这些研究将扩大有关如何 酒精肠毒性在烧伤创伤的背景下改变了肠道屏障。针对我们的肠道的研究 动物模型可以作为开发新型治疗干预措施的第一步 活跃军事和退伍军人人口烧伤的患者。此外，这项工作的意义是 超越烧伤损伤，因为肠道屏障功能障碍可能在与非烧伤相关疾病中起作用 从创伤性脑损伤到创伤后应激障碍。