HIF-1alpha and VEGF in Acetaminophen Toxicity and Repair

HIF-1α 和 VEGF 在对乙酰氨基酚毒性和修复中的作用

• 批准号: 7629666
• 负责人: Laura P James
• 金额: $ 25.21万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-24 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7629666
• 关键词: Acetaminophen; Acetylcysteine; Acute Liver Failure; Angiogenic Factor; Antidotes; Binding; Biological Markers; Biological Models; Cessation of life; Cyclosporine; Data; Development; Disease model; Dose; Event; Foundations; Future; Gene Silencing; Glutathione; Hepatic; Hepatocyte; Hepatotoxicity; Homeostasis; Human; Hypoxia; Hypoxia Inducible Factor; Incidence; Knowledge; Lead; Liver; Mediating; Mediator of activation protein; Mitochondria; Modeling; Molecular; Mus; Natural regeneration; Necrosis; Nuclear; Organ; Organogenesis; Oxidative Stress; Oxygen; Patients; Permeability; Phase; Pimonidazole; Play; Poisoning; Process; Production; Public Health; Recovery; Reporting; Research Personnel; Role; Secondary to; Staging; Technology; Testing; Time; Toxic effect; United States; Up-Regulation; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vascular System; Work; adduct; design; effective therapy; hypoxia inducible factor 1; in vivo; inhibitor/antagonist; liver cell proliferation; liver transplantation; mortality; neutralizing antibody; novel; programs; receptor; repaired; response; transcription factor; treatment effect

DESCRIPTION (provided by applicant): Acetaminophen (APAP) is the major cause of acute liver failure (ALF) in the U.S. The antidote, N- acetylcysteine (NAC), increases hepatic GSH, decreases covalent binding and is highly effective in the early stages of toxicity. However, after the onset of toxicity, NAC has limited efficacy and there is a high incidence of liver transplant or death in these patients. This proposal will investigate mechanisms of repair of APAP-induced toxicity because novel therapies are possible with augmentation of innate repair mechanisms in ALF secondary to APAP. Our preliminary studies reveal mechanisms of hepatocyte regeneration that are critical to recovery in the late stages of APAP mediated ALF. Oxidative stress, hypoxia inducible factor 1 alpha (HIF-1?) and vascular endothelial growth factor (VEGF) appear to play central roles in the liver's response to APAP toxicity. We show that HIF-1? and VEGF are dramatically increased in the livers of APAP intoxicated mice. Also, treatment with a VEGF inhibitor markedly delays hepatocyte regeneration. It is well established, in other model systems, that HIF-1? can regulate the levels of VEGF, however this has not been previously investigated in the liver. VEGF is an angiogenic factor important in organ repair. Although hypoxia is a well described mechanism of HIF-1? induction in many models, our recent data indicate that oxidative stress induces HIF-1? and is central to APAP mediated ALF. We have shown that HIF-1? is induced in freshly isolated mouse hepatocytes treated with APAP under normoxic conditions and blocked by inhibitors of oxidative stress. Using freshly isolated hepatocytes, we recently reported that APAP induced oxidative stress and mitochondrial permeability transition leading to cellular necrosis. We will test the three following hypotheses: 1) Oxidative stress leads to HIF-1? induction in APAP-mediated hepatotoxicity in mice. 2) Nuclear factor HIF-1? is critical for upregulation of VEGF synthesis in APAP toxicity in mice. 3) The interactions of VEGF and its receptors are critical to hepatocyte regeneration following APAP toxicity in mice. Lay description: This project will examine mechanisms of repair in the liver following acetaminophen toxicity in mice treated with acetaminophen. A better understanding of the recovery processes of the liver will lead to the development of new treatments for acute liver failure.

描述（由申请人提供）：对乙酰氨基酚 (APAP) 是美国急性肝衰竭 (ALF) 的主要原因。解毒剂 N-乙酰半胱氨酸 (NAC) 可增加肝脏 GSH，减少共价结合，在毒性早期阶段非常有效。然而，出现毒性后，NAC的疗效有限，并且这些患者的肝移植或死亡发生率很高。该提案将研究 APAP 诱导毒性的修复机制，因为通过增强继发于 APAP 的 ALF 的先天修复机制，新的疗法是可能的。我们的初步研究揭示了肝细胞再生机制，这对于 APAP 介导的 ALF 晚期的恢复至关重要。氧化应激、缺氧诱导因子 1 α (HIF-1?) 和血管内皮生长因子 (VEGF) 似乎在肝脏对 APAP 毒性的反应中发挥着核心作用。我们展示了HIF-1？ APAP 中毒小鼠肝脏中的 VEGF 和 VEGF 显着增加。此外，使用 VEGF 抑制剂治疗可显着延迟肝细胞再生。在其他模型系统中，HIF-1？可以调节 VEGF 的水平，但是之前尚未在肝脏中进行过研究。 VEGF 是一种对器官修复很重要的血管生成因子。尽管缺氧是 HIF-1 的一个已被充分描述的机制？在许多模型中诱导，我们最近的数据表明氧化应激诱导 HIF-1？并且是 APAP 介导的 ALF 的核心。我们已经证明了HIF-1？在常氧条件下用 APAP 处理的新鲜分离的小鼠肝细胞中诱导并被氧化应激抑制剂阻断。使用新鲜分离的肝细胞，我们最近报道 APAP 诱导氧​​化应激和线粒体通透性转变，导致细胞坏死。我们将测试以下三个假设：1）氧化应激导致HIF-1？诱导 APAP 介导的小鼠肝毒性。 2）核因子HIF-1？对于小鼠 APAP 毒性中 VEGF 合成的上调至关重要。 3) VEGF 及其受体的相互作用对于小鼠 APAP 毒性后的肝细胞再生至关重要。简单描述：该项目将研究用对乙酰氨基酚治疗的小鼠在对乙酰氨基酚中毒后肝脏的修复机制。更好地了解肝脏的恢复过程将有助于开发治疗急性肝衰竭的新疗法。