Alcohol Intoxication and Postburn Intestinal Immunity

酒精中毒和烧伤后肠道免疫

基本信息

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
项目类别：
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

项目摘要

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）：此 R01 申请是针对 NIAAA PA-12-025 的响应，旨在研究酒精暴露增强烧伤后发病机制。研究表明，与受伤时未醉酒的烧伤患者相比，烧伤时醉酒的患者更容易受到感染，发病率和死亡率明显更高。乙醇增强烧伤后发病机制的机制尚不清楚。肠道是体内细菌的主要储存库。在健康条件下，它维持着一道屏障，防止这些细菌穿过肠腔。然而，这种屏障在接触酒精（乙醇）和烧伤后会受到损害。我们发现乙醇中毒合并烧伤：1）抑制肠道相关淋巴组织[派尔氏淋巴结（PP）和肠系膜淋巴结（MLN）]Th1（IL-2和IFN-？）和Th17（IL-17和IL-1） 22)细胞因子的产生； 2) 增加肠道内IL-18的水平； 3）造成肠道组织损伤和渗漏； 4) 损伤后 24 小时内增加肠道细菌生长和细菌移位。细菌和/或其产物易位的这种增加可能会使全身炎症反应持续下去，并最终导致乙醇暴露和烧伤后的不良后果。最近的研究结果表明，Th17 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发挥着至关重要的作用。我们的研究结果表明 IL-22 和 IL-18 在维持粘膜完整性方面的作用。我们研究的总体目标是描绘乙醇与烧伤联合抑制 Th17 效应细胞因子的机制，以及 Th17 细胞因子的减少如何与烧伤相关。或没有 IL-18 会导致酒精和烧伤后肠道免疫和上皮屏障受损。我们假设“烧伤前的乙醇中毒会导致 Th17 效应细胞因子、IL-17 和 IL-22 减少，当与 IL-18 增加相结合时，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生长。”易位。”该假设将在 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。目标 1 的研究将确定烧伤前接触乙醇导致肠道 Th17 细胞因子减少的机制。目标 2 将研究烧伤前接触乙醇导致肠道渗漏增加的机制。目标 3 将研究单独恢复 IL-22 或与 IL-18 抑制相结合是否可以使抗菌肽（例如 Reg3？和 Reg3？）正常化，以及这是否可以防止乙醇暴露和烧伤后肠道细菌负荷增加及其易位。总的来说，我们的研究将对乙醇中毒与烧伤相结合破坏肠道屏障的机制产生新的见解，并可能有助于为该患者群体制定更好的治疗策略。