Sterile Hepatic Inflammation

无菌性肝脏炎症

• 批准号: 7929861
• 负责人: WAJAHAT Zafar MEHAL
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929861
• 关键词: Acetaminophen; Alcoholic Hepatitis; Antigens; Apoptotic; Caspase-1; Cells; Cessation of life; DNA; Development; Disease; Drug toxicity; Endothelial Cells; Event; Funding; Grant; Hepatic; Hepatitis; Hepatocyte; Hepatotoxicity; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-18; Knowledge; Liver; Liver diseases; Mitochondrial DNA; Molecular; Necrosis; Nuclear; Nucleic Acids; Pathway interactions; Pattern; Population; Production; Reperfusion Injury; Role; Signal Pathway; Signal Transduction; Sterility; TLR7 gene; Testing; Therapeutic; Toxic effect; Transcript; Up-Regulation; Urate; abstracting; base; cytokine; design; improved; in vivo; microbial; mouse model; non-alcoholic; nonalcoholic steatohepatitis; novel strategies; pathogen; problem drinker; protein complex; receptor

DESCRIPTION (provided by applicant): Project Summary/Abstract Pathological hepatocyte death results in a sterile inflammatory response (SIR) which amplifies the original liver injury. The SIR is an important component of injury in a wide range of diseases including acetaminophen (APAP) hepatotoxicity, as well as alcoholic and non-alcoholic steatohepatitis. The molecular mechanisms responsible for sterile inflammation in the liver are largely unknown. Hypothesis. There is a two signal requirement for the development of sterile inflammation in the liver: Signal 1) Activation of TLR 7 and 9 by mammalian nucleic acids resulting in up-regulation of pro-IL-1b and pro-IL-18 and signal 2) Activation of the inflammasome and caspapse-1 for cleavage of pro-IL-1b and pro-IL-18, and secretion of active cytokines. To examine these issues, we have used the mouse model of APAP hepatotoxicity and show that: i) IL- 1b and IL-18 are required for full APAP hepatotoxicity. ii) Activation of TLR7 and 9 is required for up-regulation of pro-IL-1b and pro-IL-18 transcripts in the liver and full APAP hepatotoxicity. iii) DNA from apoptotic hepatocytes can activate TLR9 on sinusoidal endothelial cells, and cause liver injury. iv) Components of the inflammasome (NLRP3, ASC, caspase-1) are required for full APAP hepatotoxicity. Based on this background we propose the following objectives: 1: Identify the interactions between mammalian nucleic acids and TLR 7 and 9 which result in up- regulation of pro-IL-1b and pro-lL-18. 1a) Test if ssRNA and nuclear and mitochondrial DNA from healthy, necrotic and apoptotic hepatocytes can up-regulate pro-IL-1b and pro-lL-18 in liver cell populations. 1b) Test if TLR 7 and 9 signaling is required for the effects seen in 1a. 1c) Identify the signaling pathways fromTLR7 and TLR9 which result in up-regulation of pro-IL-1b and pro-IL-18. 1d) Test if TLR7 and 9 are sufficient or required for inflammasome activation. 2: Identify the mechanisms of activation of the NLRP3 inflammasome. 2a) Determine the role of ATP and monosodium urate (MSU) in inflammasome activation in liver cell populations. 2b) Determine the role of the pannexin channel in-vivo in the APAP induced hepatic SIR. 2c) Determine the role of MSU in-vivo in the APAP induced hepatic SIR. PUBLIC HEALTH RELEVANCE: Project Narrative Chronic liver disease due to drug toxicity, alcoholic steatohepatitis (ASH), non-alcoholic hepatitis (NASH), hepatitis C and B are over-represented in the veteran population. This is due to a higher incidence of substance abuse, diabetes and exposure to needle sticks and blood products. This results in a very high degree of morbidity due to fatigue, jaundice, ankle swelling and pruritis. In addition this also results in increased mortality due to cirrhosis, hepatocellular cancer as well as liver failure. Currently there are no effective treatments these liver diseases. This is due to the fact that we have a very poor understanding of how liver inflammation and injury start in these conditions. We propose to identify the molecules in the TLR and inflammasome pathways, which are required to start the process of liver inflammation and injury. The knowledge gained from this project will therefore directly result in designing rational therapies for these conditions.

描述（由申请人提供）： 项目摘要/摘要病理肝细胞死亡导致无菌炎症反应（SIR）扩大了原始肝损伤。 SIR是多种疾病中损伤的重要组成部分，包括对乙酰氨基酚（APAP）肝毒性，以及酒精和非酒精性脂肪性肝炎。导致肝脏无菌炎症的分子机制在很大程度上未知。假设。 There is a two signal requirement for the development of sterile inflammation in the liver: Signal 1) Activation of TLR 7 and 9 by mammalian nucleic acids resulting in up-regulation of pro-IL-1b and pro-IL-18 and signal 2) Activation of the inflammasome and caspapse-1 for cleavage of pro-IL-1b and pro-IL-18, and secretion of active cytokines. 为了检查这些问题，我们使用了APAP肝毒性的小鼠模型，并表明：i）IL-1B和IL-18是完全APAP肝毒性所必需的。 ii）TLR7和9的激活是在肝脏中上调Pro-IL-1B和Pro-IL-18的上调所必需的。 iii）凋亡肝细胞的DNA可以激活正弦内皮细胞上的TLR9，并引起肝损伤。 iv）炎性体的成分（NLRP3，ASC，caspase-1）是完全APAP肝毒性所必需的。基于此背景，我们提出以下目标：1：确定哺乳动物核酸与TLR 7和9之间的相互作用，从而导致Pro-IL-1B和Pro-LL-18的调节。 1A）测试来自健康，坏死和凋亡肝细胞的ssRNA，核和线粒体DNA是否可以在肝细胞群中上调pro-IL-1B和Pro-LL-18。 1B）测试是否需要1A中看到的效果TLR 7和9信号传导。 1C）从TLR7和TLR9识别信号通路，从而导致Pro-IL-1B和Pro-IL-18的上调。 1d）测试如果TLR7和9是否足够或需要进行炎症体激活。 2：确定NLRP3炎症体激活的机制。 2A）确定ATP和单钠（MSU）在肝细胞种群中炎性体激活中的作用。 2b）确定pannexin通道在体内在APAP诱导的肝SIR中的作用。 2C）确定MSU在体体中在APAP诱导的肝SIR中的作用。 公共卫生相关性： 由于药物毒性，酒精性脂肪性肝炎（ASH），非酒精性肝炎（NASH），丙型肝炎和丙型肝炎而导致的叙事叙事慢性肝病在退伍军人人群中的代表性过高。这是由于滥用药物，糖尿病和针头棒和血液产品的发生率更高。由于疲劳，黄疸，脚踝肿胀和瘙痒，这会导致非常高的发病率。此外，由于肝硬化，肝细胞癌和肝衰竭，这还导致死亡率增加。 目前尚无这些肝脏疾病的有效治疗。这是由于我们对在这些疾病中肝脏炎症和损伤如何启动的事实非常糟糕。我们建议鉴定TLR和炎性途径中的分子，这是开始肝脏炎症和损伤过程所必需的。因此，从该项目中获得的知识将直接导致为这些条件设计合理疗法。