Effects of acute ethanol exposure on post burn intestinal immunity: role of IL-23

急性乙醇暴露对烧伤后肠道免疫的影响：IL-23 的作用

基本信息

批准号：
8602760
负责人：
Juan Luis Rendon
金额：
$ 2.87万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8602760
关键词：
Abbreviations Acute Admission activity Adult Affect Alcoholic Intoxication Alcohols Bacteria Bacterial Translocation Blood Body Surface Area Burn injury Cells Cessation of life Concanavalin A Containment Data Defensins Dendritic Cells Development Edetic Acid Enzyme-Linked Immunosorbent Assay Epithelial Cells Ethanol Fluorescence Fluorescence-Activated Cell Sorting Gut associated lymphoid tissue Homeostasis Hospitalization Hospitals Immune Immunity Immunosuppression Infection Injury Interleukin-17 Interleukins Intestines Laboratories Lipopolysaccharides Lymphocyte Lymphoid Major Histocompatibility Complex Measurable Mediating Modeling Morbidity - disease rate Mucosal Immunity Mus Nuclear Orphan Receptor Organ Pathogenesis Patient Care Patients Play Production Publishing Recombinant Interleukins Regulation Reporting Risk Role STAT protein STAT3 gene Small Intestines Stat3 protein Structure of aggregated lymphoid follicle of small intestine Th1/Th2 Differentiation Pathway Therapeutic Intervention Time Tissues Translating United States Up-Regulation alcohol exposure antimicrobial antimicrobial peptide base cytokine extracellular fetal bovine serum heat injury immune function improved in vivo interleukin-22 interleukin-23 intestinal epithelium intraperitoneal mortality mouse model novel public health relevance response therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): Alcohol is a contributing factor in post burn morbidity and mortality. Our laboratory has previously demonstrated that acute alcohol intoxication suppresses intestinal immune function and enhances bacterial translocation, yet the mechanism responsible for these observations remains unknown. Current evidence suggest that T helper (Th) 17 lymphocytes play a critical role in maintaining normal barrier function and minimizing invasion of bacteria across the intestinal epithelium. Additionally, interleukin IL-23, a cytokine released predominantly by dendritic cells, is crucial in Th17 differentiation and antimicrobial expression. Preliminary studies from our laboratory demonstrated decreased levels of Th17 effector cytokine IL-17 as well as decreased levels of the p40 subunit of IL-23 in Peyer's patches following alcohol intoxication and burn injury. Peyer's patches are small immune cell-containing lymphoid organs along the small intestine that are critical to bacterial containment. Based on these observations, we hypothesize that alcohol intoxication prior to burn injury disrupts IL-23 production from dendritic cells within Peyer'spatches, which in turn impairs Th17 effector functions and antimicrobial expression within the intestine. Three specific aims have been developed to examine this hypothesis. Aim 1 will establish the effects of acute alcohol exposure on post burn IL-23 release within the intestine and correlate these findings with altered secretion of Th17 cytokines IL-17 and IL-22 and antimicrobial expression. Aim 2 will determine if administration of recombinant IL- 23, improves intestinal Th17 effector functions and antimicrobial peptide expression following alcohol intoxication and burn injury. Aim 3 will focus on the role of STAT3 and ROR-3t activation in IL-23 mediated regulation of Th17 responses following alcohol intoxication and burn injury. Studies will be carried out using a mouse model of acute alcohol exposure and thermal injury. Overall, this proposal will yield novel data that may aid in the development of targeted therapeutic interventions for patients who sustain burn injury after exposure to alcohol. PUBLIC HEALTH RELEVANCE: Each year over 100,000 hospitalizations and 5,000 deaths within the United States are associated with burn injury, nearly half of these burn injuries are sustained under the influence of acute alcohol intoxication. These patients go on to demonstrate increased rates of infection, morbidity and mortality when compared to that of patients who were not under the influence of alcohol at the time of injury. The proposed studies will potentially provide a mechanism by which alcohol complicates burn injury and reveal valuable therapeutic targets to improve the care of patients who sustain injury following exposure to alcohol.

描述（由申请人提供）：酒精是烧伤后发病率和死亡率的促成因素。我们的实验室先前已经证明，急性酒精中毒会抑制肠道免疫功能并增强细菌易位，但是负责这些观察结果的机制仍然未知。当前的证据表明，T助手（TH）17淋巴细胞在维持正常的屏障功能和最大程度地减少肠上皮细菌的侵袭中起着关键作用。另外，白介素IL-23是一种主要由树突状细胞释放的细胞因子，在TH17分化和抗菌表达中至关重要。我们实验室的初步研究表明，Th17效应子细胞因子IL-17的水平降低，以及在酒精中毒和烧伤损伤后，IL-23的P40亚基水平降低。 Peyer的斑块是沿小肠含有小的免疫细胞淋巴器官，对细菌遏制至关重要。基于这些观察结果，我们假设在烧伤损伤之前醉酒中毒会破坏Peyer'Spatches内的树突状细胞的IL-23产生，进而破坏Th17效应子功能和肠内抗菌表达。已经开发出三个具体目标来检验这一假设。 AIM 1将建立急性酒精暴露对肠内燃烧后IL-23释放的影响，并将这些发现与Th17细胞因子IL-17和IL-17和IL-22的分泌改变以及抗菌表达相关。 AIM 2将确定重组IL-23的施用是否可以改善肠道效果功能和酒精中毒和烧伤后的抗菌肽表达。 AIM 3将重点介绍STAT3和ROR-3T激活在IL-23介导的饮酒和烧伤后Th17反应的调节中的作用。研究将使用急性酒精暴露和热损伤的小鼠模型进行研究。总体而言，该提案将产生新的数据，这可能有助于为暴露于酒精后承受烧伤的患者的靶向治疗干预措施开发。公共卫生相关性：美国每年有超过100,000次住院和5,000人死亡与烧伤有关，其中将近一半的烧伤受伤受到急性酒精中毒的影响。与受伤时不受酒精影响的患者相比，这些患者继续证明感染率，发病率和死亡率增加。拟议的研究将有可能提供一种机制，通过这种机制，酒精使烧伤损伤复杂并揭示了有价值的治疗靶标，以改善暴露于酒精后维持损伤的患者的护理。