Alcohol Intoxication and Postburn Intestinal Immunity

酒精中毒和烧伤后肠道免疫

• 批准号: 8599202
• 负责人: Mashkoor A Choudhry
• 金额: $ 50.54万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-10 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8599202
• 关键词: Abbreviations; Affect; Alcohol consumption; Alcoholic Intoxication; Alcohols; Antibodies; Apoptosis; Aryl Hydrocarbon Receptor; Bacteria; Bacterial Translocation; Body Surface Area; Burn injury; Colony-forming units; Complication; Critical Illness; Disease; Epithelial; Ethanol; Exhibits; Functional disorder; Funding Opportunities; Goals; Growth; Gut associated lymphoid tissue; Homeostasis; Host Defense; Hour; Hypoxia; Immune; Immunity; Impaired wound healing; Impairment; Infection; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Interferons; Interleukin-17; Interleukin-18; Interleukin-2; Interleukins; Intestines; Janus kinase; Laboratories; Length of Stay; Link; Lipopolysaccharides; Lymphocyte; Lymphoid; Lymphoid Tissue; Mesentery; Morbidity - disease rate; Mucosal Immunity; Multiple Organ Failure; Mus; National Institute on Alcohol Abuse and Alcoholism; Natural regeneration; Organ; Orphan; Outcome; Pathogenesis; Patients; Permeability; Play; Polymerase Chain Reaction; Production; Proliferating Cell Nuclear Antigen; Protein Tyrosine Kinase; Proteins; Recombinants; Relative (related person); Reporting; Retinoic Acid Receptor; Role; STAT protein; Sepsis; Sepsis Syndrome; Stat3 protein; Structure of aggregated lymphoid follicle of small intestine; Testing; Therapeutic; Tight Junctions; Time; Tissues; Transforming Growth Factors; Tretinoin; United States; alcohol exposure; antimicrobial peptide; body system; cytokine; effective therapy; experience; gastrointestinal epithelium; immune function; injured; insight; interleukin-22; intraperitoneal; islet; lymph nodes; mortality; mouse model; novel; patient population; prevent; public health relevance; receptor; response; restoration

DESCRIPTION (provided by applicant): This R01 application in response to NIAAA PA-12-025 is to investigate the mechanism by which alcohol exposure enhances post burn pathogenesis. Studies have shown that patients who are intoxicated at the time of burn injury are more susceptible to infection and exhibit significantly higher morbidity and mortality compared to burn patients who are not intoxicated at the time of injury. The mechanism by which ethanol enhances post burn pathogenesis remains largely unclear. Gut is the major reservoir of bacteria within the body; under healthy conditions it maintains a barrier which prevents these bacteria from crossing the intestinal lumen. However, this barrier is compromised following alcohol (ethanol) exposure and burn injury. We found that ethanol intoxication combined with burn injury: 1) suppresses gut associated lymphoid [Peyer's patches (PP) and mesenteric lymph nodes (MLN)] Th1 (IL-2 and IFN-?), and Th17 (IL-17 and IL-22) cytokine production; 2) increases IL-18 levels in the gut; 3) causes gut tissue damage and leakiness; and 4) increases gut bacterial growth and bacterial translocation within 24 hours after injury. Such an increase in the translocation of bacteria and/or their products may perpetuate the systemic inflammatory response and ultimately contribute to poorer outcomes following ethanol exposure and burn injury. Recent findings indicate that Th17 lymphocytes and their effector cytokines, IL-17 and IL-22, play a crucial role in maintaining mucosal immunity and barrier integrity. Our findings suggest a role for IL-22 and IL-18 in maintaining mucosal integrity The overall goal of our studies is to delineate the mechanism(s) by which ethanol combined with burn injury suppresses Th17 effector cytokines and how this decrease in Th17 cytokines with or without IL-18 contributes to impaired gut immunity and epithelial barrier following alcohol and burn injury. We hypothesize that "Ethanol intoxication prior to burn injury results in decreased Th17 effector cytokines, IL-17 and IL-22, which when combined with an increase in IL-18 compromises gut immunity and barrier integrity, facilitating gut bacterial growth and subsequent gut bacterial translocation." The hypothesis will be tested in 3 Aims using a well-established mouse model of ethanol intoxication and burn injury. Studies in Aim 1 will determine the mechanism(s) by which ethanol exposure prior to burn injury results in decreased Th17 cytokines in the intestine. Aim 2 will investigate the mechanism(s) by which ethanol exposure prior to burn injury results in increased gut leakiness. Aim 3 will investigate whether IL-22 restoration alone or in combination with IL-18 inhibition normalizes antimicrobial peptides (e.g. Reg3? and Reg3?) and whether this prevents increased gut bacterial load and their translocation following ethanol exposure and burn injury. Overall, our studies will yield novel insights into the mechanism by which ethanol intoxication combined with burn injury disrupts the gut barrier and may help in developing better therapeutic strategies for this patient population.

描述（由申请人提供）：响应NIAAA PA-12-025的R 01申请旨在研究酒精暴露增强烧伤后发病机制的机制。研究表明，与受伤时未中毒的烧伤患者相比，在烧伤时中毒的患者更容易感染，并表现出显著更高的发病率和死亡率。乙醇增强烧伤后发病机制的机制在很大程度上仍不清楚。肠道是体内细菌的主要储存库;在健康条件下，它保持着一个屏障，防止这些细菌穿过肠腔。然而，这种屏障在酒精（乙醇）暴露和烧伤后受到损害。我们发现乙醇中毒合并烧伤：1）抑制肠道相关淋巴结[派伊尔集合淋巴结（PP）和肠系膜淋巴结（MLN）] Th 1（IL-2和IFN-？），和Th 17（IL-17和IL-22）细胞因子产生; 2）增加肠道中的IL-18水平; 3）引起肠道组织损伤和渗漏;和4）在损伤后24小时内增加肠道细菌生长和细菌移位。细菌和/或其产物移位的这种增加可能使全身炎症反应持续存在，并最终导致乙醇暴露和烧伤后的不良结局。最近的研究结果表明，Th 17淋巴细胞及其效应细胞因子IL-17和IL-22在维持粘膜免疫和屏障完整性方面起着至关重要的作用。我们的研究结果表明IL-22和IL-18在维持粘膜完整性中的作用。我们研究的总体目标是描述乙醇联合烧伤抑制Th 17效应细胞因子的机制，以及在有或没有IL-18的情况下，Th 17细胞因子的这种减少如何导致酒精和烧伤后肠道免疫和上皮屏障受损。我们假设“烧伤前的乙醇中毒导致Th 17效应细胞因子IL-17和IL-22减少，当与IL-18增加结合时，会损害肠道免疫和屏障完整性，促进肠道细菌生长和随后的肠道细菌移位。“这一假设将在3个目标中使用成熟的乙醇中毒和烧伤小鼠模型进行测试。目的1中的研究将确定烧伤前乙醇暴露导致肠中Th 17细胞因子减少的机制。目的2将研究烧伤前乙醇暴露导致肠漏增加的机制。目的3将研究单独或与IL-18抑制组合的IL-22恢复是否使抗微生物肽（例如Reg 3？（Reg3）以及这是否阻止了乙醇暴露和烧伤后肠道细菌负荷的增加及其移位。总的来说，我们的研究将产生新的见解乙醇中毒结合烧伤破坏肠道屏障的机制，并可能有助于为这一患者群体制定更好的治疗策略。