IL-27 receptor signaling in the maintenance of intestinal barrier after ethanol and burn injury

IL-27 受体信号传导在乙醇和烧伤后维持肠道屏障中的作用

• 批准号: 10179350
• 负责人: Marisa Luck
• 金额: $ 3.28万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10179350
• 关键词: Admission activity; Alcoholic Intoxication; Alcohols; Anti-Inflammatory Agents; Antigen-Presenting Cells; Bacteria; Bacterial Translocation; Behavior; Blood alcohol level measurement; Burn injury; Cell physiology; Cells; Cessation of life; Clinical; Clostridium difficile; Colitis; Cytokine Signaling; Data; Epithelial Cell Proliferation; Epithelial Cells; Ethanol; Flow Cytometry; Functional disorder; Goals; Health; Homeostasis; Hospitalization; Hour; Hypoxia; Hypoxia Inducible Factor; IL27RA gene; IL6ST gene; Immune; Immune System Diseases; Immune response; Impairment; Infection; Inflammation; Injury; Interleukins; Intestinal Diseases; Intestinal permeability; Intestines; Knockout Mice; Lamina Propria; Lead; Leaky Gut; Length of Stay; Life; Liquid substance; Maintenance; Mediating; Mediator of activation protein; Medical; Messenger RNA; Modeling; Morbidity - disease rate; Multiple Organ Failure; Mus; Organoids; Outcome; Pathogenesis; Patients; Phosphorylation; Population; Production; Proteins; Receptor Signaling; Research; Resuscitation; Risk-Taking; Role; STAT1 gene; STAT3 gene; Sepsis; Signal Transduction; Signaling Molecule; Small Intestines; Testing; Tight Junctions; Time; Transcript; Trauma; Traumatic injury; adverse outcome; base; cytokine; experience; gastrointestinal; gastrointestinal system; healing; hypoperfusion; improved; improved outcome; in vivo; infection rate; inflammatory disease of the intestine; inhibitor/antagonist; insight; intestinal barrier; intestinal epithelium; mRNA Expression; mortality; mouse model; novel; novel therapeutic intervention; prevent; protein expression; receptor; receptor expression; restoration

Project Summary/Abstract The goal of this project is to better understand how interleukin-27 (IL-27) signaling in intestinal epithelial cells (IEC) can promote intestinal barrier integrity in the setting of ethanol intoxication and burn injury. Burn injuries account for 40,000 hospitalizations every year, with nearly 50% of patients having detectable blood alcohol levels at the time of admission. Patients intoxicated at the time of burn injury have worse clinical outcomes, including longer hospital stays, increased rates of infection, and increased morbidity and mortality. Detrimental sequelae of burn injuries are the result of the breakdown in the gut barrier, which normally encloses the largest reservoir of bacteria and harmful bacterial products. Ethanol intoxication at the time of burn injury exacerbates this post-burn pathogenesis, leading to exacerbated gut barrier dysfunction and leakiness. This gut barrier breakdown leads to multiple organ failure, sepsis, and death following injury. A major contributing factor to gut leakiness is attributed to hypoxic conditions in the gut, leading to stabilization of hypoxia inducible factor 1a (HIF1a). Our lab has previously found that inhibition of HIF1a with PX-478 leads to improved outcomes in ethanol intoxication and burn injury, including improved gut transit, decreased gut permeability, and reduced inflammation. However, the mechanism by which this occurs is unknown. We have also found that expression of the IL-27 receptor was restored in IECs following inhibition of HIF1a following ethanol intoxication and burn injury. Ethanol intoxication and burn injury led to reduced IL-27 producing cells in the lamina propria, which is accompanied by reduced IL-27 receptor expression in IECs. IL-27 has been implicated in restoring intestinal barrier integrity in other models of intestinal inflammation, therefore leading us to hypothesize that restoring IL- 27 signaling following ethanol intoxication and burn injury will lead to improved barrier integrity. In Aim 1, we will determine perturbations in IL-27 signaling in the intestine following HIF1a inhibition in ethanol intoxication and burn injury. In Aim 2, we will elucidate the mechanism by which IL-27 signaling restores intestinal epithelial barrier integrity by observing changes in phosphorylation of downstream signaling molecules STAT1/STAT3, IEC proliferation, and tight junction expression. Overall, this study will aid in our understanding of how we can restore intestinal barrier function following ethanol intoxication and burn injury.

项目总结/摘要 本项目的目标是更好地了解肠上皮细胞中白细胞介素-27（IL-27）信号转导 (IEC)在乙醇中毒和烧伤的情况下可以促进肠屏障的完整性。烧伤 每年有4万人住院，近50%的患者血液中含有酒精 入学时的水平。在烧伤时中毒的患者临床结果更差， 包括更长的住院时间、增加的感染率以及增加的发病率和死亡率。有害 烧伤的后遗症是肠道屏障破坏的结果，肠道屏障通常封闭最大的 储存细菌和有害细菌产物。烧伤时乙醇中毒加重 这种烧伤后的发病机制，导致肠道屏障功能障碍和泄漏加剧。这个肠道屏障 分解导致多器官衰竭、败血症和损伤后死亡。一个主要的促成因素， 渗漏是由于肠道中的缺氧条件，导致缺氧诱导因子1a的稳定 （HIF 1a）。我们的实验室先前发现，用PX-478抑制HIF 1a可改善 乙醇中毒和烧伤，包括改善肠道运输，降低肠道通透性， 炎症然而，这种情况发生的机制尚不清楚。我们还发现， 在乙醇中毒和烧伤后抑制HIF 1a后，IEC中IL-27受体的恢复 损伤乙醇中毒和烧伤导致固有层中产生IL-27的细胞减少， 伴随着IEC中IL-27受体表达的减少。IL-27与恢复肠道 在其他肠道炎症模型中的屏障完整性，因此导致我们假设，恢复IL- 乙醇中毒和烧伤后的27信号传导将导致屏障完整性的改善。目标1： 将确定乙醇中毒中HIF 1a抑制后肠中IL-27信号传导的扰动 和烧伤。在目标2中，我们将阐明IL-27信号转导恢复肠上皮细胞的机制， 通过观察下游信号分子STAT 1/STAT 3磷酸化的变化， IEC增殖和紧密连接表达。总的来说，这项研究将有助于我们了解我们如何能够 恢复酒精中毒和烧伤后的肠屏障功能。