Multi-organ Inflammatory Responses after Burn Trauma

烧伤后多器官炎症反应

• 批准号: 10683081
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683081
• 关键词: Accounting; Acute Respiratory Distress Syndrome; Admission activity; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Intoxication; Alcohols; Animal Model; Architecture; Attenuated; Bacteria; Biological Markers; Blood; Blood Circulation; Burn Trauma; Burn injury; Characteristics; Circulation; Clinical; Cutaneous; Development; Disease; Distal; Endothelial Cells; Endotoxins; Enzymes; Epithelial Cells; Epithelium; Excess Mortality; 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; 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; Persons; Play; Pneumonia; Post-Traumatic Stress Disorders; Predisposition; Process; Production; Proteins; Pulmonary Edema; Pulmonary Inflammation; Pulmonary alveolar structure; Recording of previous events; Respiratory Failure; 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; active duty; acute hypoxemic respiratory failure; alcohol exposure; biomarker identification; body system; burn wound; chemokine; circulating biomarkers; clinically relevant; clinically significant; combat; commensal bacteria; cost; cytokine; cytokine release syndrome; drinking; functional improvement; improved; indexing; inhibitor; intestinal barrier; intestinal epithelium; kinase inhibitor; leukocyte activation; lung injury; military veteran; mortality; mouse model; novel therapeutic intervention; opportunistic pathogen; pulmonary function; repaired; response; restoration; severe burns; 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，不仅影响皮肤，还会对多个器官造成损害