Alcohol Intoxication and Postburn Intestinal Immunity

酒精中毒和烧伤后肠道免疫

• 批准号: 8054760
• 负责人: Mashkoor A Choudhry
• 金额: $ 25.44万
• 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 2013-07-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8054760
• 关键词: Acute; Admission activity; Adult; Alcoholic Intoxication; Alcohols; Animals; Antibiotics; Antibodies; Appearance; Bacteria; Bacterial Translocation; Blood; Blood Circulation; Burn injury; Cell physiology; Cessation of life; Consumption; Containment; Decontamination; Dendritic Cells; Development; Dextrans; Edema; Enzymes; Event; Exhibits; Experimental Models; Fluorescein; Functional disorder; Goals; Hospitals; IL18 gene; Immune; Immunity; Infection; Injury; Interferons; Interleukin-10; Interleukin-12; Interleukin-18; Interleukin-2; Interleukin-4; Intestines; Isothiocyanates; Laboratories; Lead; Link; Lymphoid; MAPK8 gene; Measurable; Measurement; Measures; Mediating; Mesentery; Mitogen-Activated Protein Kinases; Modeling; Molecular Biology Techniques; Morbidity - disease rate; Organ; Pathogenesis; Patients; Permeability; Play; Production; Rattus; Recombinants; Research Personnel; Role; STAT protein; Signal Transduction; Small Intestines; Source; Structure of aggregated lymphoid follicle of small intestine; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Time; Tissues; Transducers; Up-Regulation; cytokine; design; dextran; experience; injured; insight; interleukin-1beta-converting enzyme inhibitor; lymph nodes; macrophage; mortality; novel; patient population; prevent; programs; restoration

DESCRIPTION (provided by applicant): Alcohol (EtOH) intoxication remains a major factor in post-burn pathogenesis. Recent studies from our laboratory have shown that acute EtOH intoxication before burn injury results in: 1) decreased intestinal lymphoid [Peyer's patches (PP) and mesenteric lymph nodes (MLN)] T cell proliferation, IL-2 and IFN-y production; 2) decreased MLN IL-12 production; 3) increased PP and MLN IL-18 production; 4) increased intestinal permeability; and 5) increased bacterial accumulation in MLN. Treatment of rats with Ac-YVAD- CHO, (5 mg/kg), an inhibitor of Caspase-1 (an enzyme that converts pro-IL-18 to mature IL-18), prevents the EtOH and burn-mediated decrease in MLN IFN-y production and the development of intestinal edema. These preliminary findings collectively suggest that IL-18 up-regulation together with a decrease in IL-12 production plays a role in altered intestinal immunity and barrier function following EtOH intoxication and burn injury. Previous studies have suggested that impaired intestinal barrier function and subsequent release of bacteria and their products play significant roles in post-burn pathogenesis. Therefore the overall goal of the proposed studies is to delineate mechanism responsible for impaired intestinal immunity and barrier function following EtOH intoxication and burn injury. We hypothesize that IL-18 up-regulation in the absence of IL-12 production in intestinal lymphoid organs following EtOH intoxication and burn injury results in decreased intestinal immunity and impaired barrier function. Using a rat model of acute EtOH intoxication and burn injury, studies in Specific Aim 1 will characterize the source (macrophage/dendritic cell) of altered IL-18 and IL-12 and determine whether IL-12 restitution alone by administering recombinant IL-12 or in combination with IL-18 inhibition by neutralizing anti-IL18 antibody prevents the: 1) suppression of intestinal immunity, and 2) impaired intestinal barrier function following EtOH intoxication and burn injury. Intestinal immunity will be determined by measuring PP and MLN T cell proliferation and cytokine profile (IL- 2, IFN-y, IL-4 and IL-10 production). Intestinal barrier functions will be measured by determining intestinal permeability and by quantifying translocated bacteria in MLN. In Specific Aim 2 studies using approaches of selective decontamination of intestine with antibiotics prior to EtOH intoxication and burn injury will determine whether intestinal bacteria are critical to IL-18/IL-12-mediated alterations in intestinal immunity and barrier function. Finally, studies in Specific Aim 3 will determine whether Mitogen Activated Protein Kinase (Erk-1/2, p-38, JNK) and/or Signal Transducer and Activator Proteins (STAT-4 and -6) are involved in signaling IL-18/IL- 12-mediated suppression of PP and MLN T cell functions following EtOH intoxication and burn injury. Our studies delineating mechanism of impaired intestinal immunity and barrier function would help in designing approaches for treatment of burn patients who sustained injury under the influence of EtOH intoxication.

描述（由申请人提供）：酒精（EtOH）中毒仍然是烧伤后发病机制的主要因素。本实验室最近的研究表明，烧伤前急性EtOH中毒导致：1）肠淋巴[派伊尔集合淋巴结（PP）和肠系膜淋巴结（MLN）] T细胞增殖、IL-2和IFN-γ产生减少; 2）MLN IL-12产生减少; 3）PP和MLN IL-18产生增加; 4）肠通透性增加; 5）MLN中细菌积累增加。用Ac-YVAD- CHO（5 mg/kg）（半胱天冬酶-1（一种将pro-IL-18转化为成熟IL-18的酶）的抑制剂）治疗大鼠，可预防EtOH和烧伤介导的MLN IFN-γ产生减少和肠水肿的发生。这些初步研究结果共同表明，IL-18上调与IL-12产生减少一起在EtOH中毒和烧伤后肠道免疫和屏障功能改变中起作用。以往的研究表明，肠屏障功能受损和随后的细菌及其产物的释放在烧伤后的发病机制中起重要作用。因此，拟定研究的总体目标是描述EtOH中毒和烧伤后肠道免疫和屏障功能受损的机制。我们推测，在乙醇中毒和烧伤后肠淋巴器官中IL-12产生缺乏的情况下，IL-18上调导致肠道免疫力下降和屏障功能受损。使用急性乙醇中毒和烧伤大鼠模型，具体目标1中的研究将描述来源（巨噬细胞/树突状细胞），并确定单独通过施用重组IL-12或与通过中和抗IL-18抗体的IL-18抑制组合的IL-12恢复是否防止：1）肠免疫抑制，和2）EtOH中毒和烧伤后肠屏障功能受损。将通过测量PP和MLN T细胞增殖和细胞因子谱（IL- 2、IFN-γ、IL-4和IL-10产生）来确定肠免疫。将通过测定肠通透性和定量MLN中的易位细菌来测量肠屏障功能。在特定目标2研究中，在EtOH中毒和烧伤之前使用抗生素选择性肠道去污方法将确定肠道细菌是否对IL-18/IL-12介导的肠道免疫和屏障功能改变至关重要。最后，特定目标3中的研究将确定有丝分裂原活化蛋白激酶（Erk-12、p-38、JNK）和/或信号转导和激活蛋白（STAT-4和STAT-6）是否参与EtOH中毒和烧伤后IL-18/IL- 12介导的PP和MLN T细胞功能抑制的信号传导。我们的研究揭示了肠道免疫和屏障功能受损的机制，将有助于设计治疗烧伤患者在EtOH中毒的影响下持续受伤的方法。