Influence of Ah Receptor Ligands on Inflammatory Respons

Ah 受体配体对炎症反应的影响

• 批准号: 7064100
• 负责人: PATRICIA E GANEY
• 金额: $ 30.2万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7064100
• 关键词: DNA methylation; aromatic hydrocarbon receptor; benzofurans; carbopolycyclic compound; cell line; computational biology; dioxins; environmental toxicology; fatty liver; gel mobility shift assay; gene expression; halobiphenyl /halotriphenyl compound; heparin; hepatotoxin; immune response; immunotoxicity; inflammation; laboratory mouse; lipopolysaccharides; microarray technology; model design /development; molecular biology; neutrophil; plasminogen activator inhibitors; prostaglandin endoperoxide synthase; toxicant interaction; tumor necrosis factor alpha

The factors that cause normally harmless episodes of inflammation to culminate in disease are largely unknown but likely include genetic and environmental influences. Exposure to environmental chemicals such as aryl hydrocarbon receptor (AhR) ligands could contribute to individual susceptibility to disease by enhancing inflammatory responses or by providing a stimulus that precipitates injury in the presence of inflammation. Indeed, in preliminary studies, mice developed liver injury when coexposed to TCDD (2,3,7,8- tetrachlorodibenzo-p-dioxin) and the inflammatory stimulus, lipopolysaccharide (LPS), each at doses that alone did not cause liver damage. The goal of the proposed research is to test the hypothesis that Ah receptor ligands enhance inflammatory responses that can lead to tissue injury. Consistent with the overall goal of the Program Project, the tissue of interest for this project is liver. This hypothesis will be tested by first evaluating the development of LPS-induced inflammation in mice exposed to AhR ligands and by delineating the dose-response relationship for AhR ligand-induced liver injury in the absence and presence of inflammation. The AhR ligands to be used are TCDD and 3,3',4,4',5-pentachlorobiphenyl (PCB 126). Mice will be treated with AhR ligands alone or in combination at doses that are not hepatotoxic. They will then be treated with a small dose of LPS that induces inflammation but alone does not cause liver injury. Markers of inflammation and liver injury will be assessed and time-courses and dose-response relationships established. Global changes in hepatic gene expression and DMA methylation in these dose-response and time-course studies will be determined by microarray analysis and will be compared to biochemical and histological changes in liver as well as to markers of inflammation. Both neutrophils and the hemostatic system, including plasminogen activator inhibitor-1 (PAI-1), are critical to liver injury in many models of chemical-inflammation interactions. To begin to understand inflammatory mediators that contribute to liver injury during AhR-inflammation interactions, the roles of neutrophils and components of the hemostatic system will be investigated in mice exposed to TCDD in the presence of inflammation. Tumor necrosis factor alpha (TNF) is a proinflammatory cytokine that is reported to mediate LPS-induced increases in expression of PAI-1 in vivo. In preliminary studies treatment of mice with either TCDD or LPS increased serum concentration of PAI-1 expression, but the combination had a synergistic effect. Accordingly, a computational description of the biochemical pathways by which AhR ligands induce changes in expression of PAI-1 in the absence and presence of inflammation will be developed. The results of these studies collectively will provide information about consequences of the interactions between inflammatory responses and AhR ligands and about molecular mechanisms involved in this interaction.

导致通常无害发炎发作的因素在很大程度上是在疾病中达到高潮的 未知但可能包括遗传和环境影响。暴露于环境化学物质 由于芳基烃受体（AHR）配体可能会导致个人对疾病的易感性 增强炎症反应或通过提供在存在下造成伤害的刺激 炎。实际上，在初步研究中，与TCDD共同实现时，小鼠出现肝损伤（2,3,7,8-- 四氯二苯二氧蛋白）和炎症性刺激，脂多糖（LPS），每种剂量都以剂量为单位 一个人不会造成肝脏损害。拟议研究的目的是检验AH的假设 受体配体增强了可能导致组织损伤的炎症反应。与整体一致 该计划项目的目标是该项目感兴趣的组织是肝脏。该假设将首先检验 评估暴露于AHR配体的小鼠中LPS诱导的炎症的发育并通过描绘 在不存在和存在的情况下 炎。要使用的AHR配体是TCDD和3,3'，4,4'，5-五氯苯基（PCB 126）。老鼠 将单独使用AHR配体处理，或以不具有肝毒性的剂量结合使用。然后他们会 用少量诱发炎症但单独的LPS治疗不会引起肝损伤。标记 炎症和肝损伤将评估，时间库和剂量反应关系 已确立的。这些剂量反应中的肝基因表达和DMA甲基化的全球变化 时间表研究将通过微阵列分析确定，并将与生化和 肝脏的组织学变化以及炎症标志物。中性粒细胞和止血 在许多模型中，包括纤溶酶原激活剂1（PAI-1）在内的系统对肝损伤至关重要 化学感染相互作用。开始了解有助于肝脏的炎症介质 AHR炎症相互作用，中性粒细胞和止血成分的作用 在炎症存在下暴露于TCDD的小鼠中，将研究系统。肿瘤坏死 因子α（TNF）是一种促炎细胞因子，据报道介导LPS诱导的增加的增加 体内PAI-1的表达。在初步研究中，用TCDD或LPS治疗小鼠会增加 PAI-1表达的血清浓度，但组合具有协同作用。因此， AHR配体诱导表达变化的生化途径的计算描述 在不存在和存在炎症的情况下，PAI-1的速度将被发展。这些研究的结果 总体将提供有关炎症反应之间相互作用的后果的信息 和AHR配体以及有关这种相互作用涉及的分子机制。