Role of Early Growth Response Factor-1 in Cholestatic Liver Injury

早期生长反应因子 1 在胆汁淤积性肝损伤中的作用

• 批准号: 7259929
• 负责人: Bryan L Copple
• 金额: $ 30.14万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7259929
• 关键词: Acids; Bile Acids; Bile fluid; Binding; Cell Adhesion Molecules; Cholestasis; Chronic; Condition; Development; Disease; Epidermal Growth Factor Receptor; Excretory function; Genes; Goals; Growth; Hepatic; Hepatocyte; Human; Inflammation; Inflammatory; Injury; Intercellular Adhesion Molecules; Intercellular adhesion molecule 1; Knockout Mice; Link; Liver; Liver Fibrosis; Liver diseases; Macrophage Inflammatory Protein-1; Mediating; Mediator of activation protein; Mitogen-Activated Protein Kinases; Molecular; Mus; Pathogenesis; Pathway interactions; Patients; Poison; Process; Production; Proteins; Research Personnel; Response Elements; Role; Serum; Signal Transduction; Staging; Testing; Time; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Up-Regulation; base; bile duct; chemokine; human TNF protein; insight; macrophage inflammatory protein 2; neutrophil; novel; programs; promoter; response; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): The overall goal of this proposal is to elucidate the mechanism by which cholestasis triggers production of proinflammatory mediators in the liver. Cholestatic liver disease arises when excretion of bile acids from the liver is interrupted. This results in the accumulation of bile acids in the liver, hepatic inflammation, and hepatocyte injury. The pathogenesis of hepatocyte injury during cholestasis depends in part on the release of proinflammatory mediators that cause neutrophils to accumulate in the liver and become activated to damage hepatocytes. Interestingly, inflammation associated with cholestasis occurs independently of tumor necrosis factor-a or interteukin-1, suggesting that this process is regulated by a novel, previously undescribed mechanism. Our preliminary studies indicate that the transcription factor, early growth response factor-1 (Egr-1), is critical for this process. Egr-1 is rapidly upregulated in hepatocytes during cholestasis. Upregulation of Egr-1 appears to be mediated directly by bile acids, since exposure of primary mouse hepatocytes to pathological concentrations of bile acids upregulates Egr-1. Our studies show further that upregulation of macrophage inflammatory protein-2, intercellular adhesion molecule-1, neutrophil accumulation, and hepatocyte injury are dramatically reduced in Egr-1 knockout mice with cholestasis. These preliminary results suggest that upregulation of Egr-1 in hepatocytes is vital for the development of neutrophil-dependent inflammatory liver injury. Furthermore, these studies indicate that Egr-1 provides the critical link between elevated concentrations of bile acids and the production of proinflammatory mediators in liver. Therefore, the main hypothesis of this proposal is that during early stages of cholestasis, elevated concentrations of bile acids upregulate Egr-1 in hepatocytes, which increases expression of proinflammatory mediators that cause neutrophils to accumulate in the liver and become activated to damage hepatocytes. The studies in this proposal aim to test this hypothesis by: (1) elucidating the molecular mechanism(s) by which bile acids upregulate Egr-1 in hepatocytes, (2) determining whether Egr-1 regulates proinflammatory mediator expression by hepatocytes, and (3) determining whether bile acids increase proinflammatory mediator expression by hepatocytes through Egr-1-dependent mechanisms. A greater understanding of the molecular mechanism(s) by which Egr-1 mediates hepatocellular injury during cholestasis could provide insight into ways to treat this disease in humans. Furthermore, since bile acid concentrations are increased in several types of liver disease in humans, this pathway could also prove to be an important, general mechanism of inflammatory injury in the liver.

描述(由申请人提供)：本提案的总体目标是阐明胆汁淤积触发肝脏促炎介质产生的机制。胆汁淤积性肝病是当胆汁酸从肝脏排泄中断时发生的。这会导致胆汁酸在肝脏中积聚，导致肝脏炎症和肝细胞损伤。胆汁淤积时肝细胞损伤的发病机制部分依赖于促炎症介质的释放，这些介质导致中性粒细胞在肝脏中积聚，并被激活以损害肝细胞。有趣的是，与胆汁淤积相关的炎症独立于肿瘤坏死因子-a或白细胞介素1而发生，这表明这一过程受一种新的、以前未描述的机制调控。我们的初步研究表明，转录因子早期生长反应因子-1(Egr-1)在这一过程中起着关键作用。在胆汁淤积过程中，EGR-1在肝细胞中迅速上调。由于原代小鼠肝细胞暴露于病理浓度的胆汁酸使Egr-1上调，因此Egr-1的上调似乎是由胆汁酸直接介导的。我们的研究进一步表明，在Egr-1基因敲除的胆汁淤积症小鼠中，巨噬细胞炎症蛋白-2、细胞间黏附分子-1、中性粒细胞聚集和肝细胞损伤的上调显著减少。这些初步结果表明，肝细胞中Egr-1的上调在中性粒细胞依赖的炎性肝损伤的发生发展中起着至关重要的作用。此外，这些研究表明，Egr-1在胆汁酸浓度升高和肝脏中促炎介质的产生之间提供了关键联系。因此，这一建议的主要假设是，在胆汁淤积的早期阶段，胆汁酸浓度升高会上调肝细胞中的Egr-1，这会增加促炎症介质的表达，导致中性粒细胞在肝脏中积聚，并被激活以损害肝细胞。本研究的目的是验证这一假说：(1)阐明胆汁酸上调肝细胞内Egr-1表达的分子机制(S)，(2)确定Egr-1是否调节肝细胞促炎介质的表达，以及(3)确定胆汁酸是否通过Egr-1依赖的机制促进肝细胞促炎症介质的表达。更好地理解Egr-1在胆汁淤积过程中介导肝细胞损伤的分子机制(S)可以为人类治疗这种疾病的方法提供洞察力。此外，由于在人类几种类型的肝病中胆汁酸浓度升高，这一途径也可能被证明是肝脏炎症损伤的一个重要的、一般的机制。