Oxidative damage and proteasome activity: Role of opioid in HIV-HCV infection

氧化损伤和蛋白酶体活性：阿片类药物在 HIV-HCV 感染中的作用

• 批准号: 7777398
• 负责人: NAZIRA EL-HAGE
• 金额: $ 14.8万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777398
• 关键词: Affect; Antioxidants; Antiviral Agents; Apoptosis; Biological Assay; Blood-Borne Pathogens; Cell Death; Cells; Chronic; Chronic Hepatitis C; Cirrhosis; Communicable Diseases; Comorbidity; Data; Development; Disease; Disease Progression; Down-Regulation; Drug usage; Event; Extrahepatic; Free Radicals; Future; Generations; HIV; HIV-1; Hepatic; Hepatitis C; Hepatitis C virus; Hepatitis Viruses; Hepatocyte; Hepatotoxicity; Heroin; Human; Immune response; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injecting drug user; Injection of therapeutic agent; Injury; Iron Overload; Ischemia; Lead; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Mediating; Mediator of activation protein; Morphine; Morphine Abuse; Mus; Natural Immunity; Nitric Oxide; Nitrogen; Opiates; Opioid; Opioid Receptor; Oxidants; Oxidative Stress; Oxycodone; Oxygen; Persons; Phagocytosis; Pharmaceutical Preparations; Physiological; Play; Predisposition; Primary carcinoma of the liver cells; Principal Investigator; Process; Production; Proteins; Reactive Oxygen Species; Recruitment Activity; Reperfusion Therapy; Role; Signal Transduction; Staging; System; Testing; Toxic effect; Toxin; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; United States; Viral; Viral Proteins; Viral hepatitis; Viremia; Virus Diseases; Virus Replication; base; chemokine; cytokine; high risk; macrophage; migration; multicatalytic endopeptidase complex; neutrophil; novel; oxidative damage; programs; public health relevance; response; transmission process

DESCRIPTION (provided by applicant): Among injection drug users (IDUs), human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are the two blood-borne pathogens most commonly transmitted. About 25% of HIV infected persons in the United States are also infected with Hepatitis C virus (HCV) while the incidence of HCV infection among persons who acquired HIV from injection drug use approaches 90%. Although the role of HCV in progression of HIV disease remains unclear, co-infection with HIV infection has been associated with accelerated progression of chronic hepatitis C towards cirrhosis and end stage liver disease. The mechanisms responsible for more rapid progression of hepatic disease and increased HCV viremia in individuals co-infected with HIV-1 are not fully understood. Viral infection rapidly triggers intracellular signaling events, leading to an innate cellular antiviral state, and damage to the innate immunity may generate a favorable microenvironment for persistent viral infection. Most liver damage associated with HCV infection is mediated by innate and acquired immune responses. Morphine, the major metabolite of heroin, is the most common opiate drug and preferentially activates <-opioid receptors (MOR). Chronic morphine use and abuse has been shown to impair host innate immune responses, including the production of chemokines and pro-inflammatory cytokines, phagocytosis, and neutrophil migration, which can lead to increased susceptibility to bacterial and viral infections. Morphine, through down- regulation of IFN-1 mediated innate immunity, favors HCV replication in hepatic cells. Chemokines and pro- inflammatory cytokines are important mediators of the immune response and the inflammatory process. More specifically, the pro-inflammatory cytokine, tumor necrosis factor-1 (TNF-1) plays an integral role in hepatocyte injury and cell death in a number of pathophysiological states such as liver injury from toxins, ischemia/ reperfusion, and hepatitis virus. In addition, morphine-induced oxidative damage has been hypothesized to contribute too many of the systemic manifestations of liver disease and hepatotoxicity experimentally shown in mice and in heroin abusers. Activation of MOR can trigger increased production of reactive oxygen species (ROS) and apoptosis. Using a recently established in vitro HCV infection system, we will test the hypothesis that opioids contributes to HCV disease progression by disrupting the response of hepatocytes to HCV and HIV through 1) increase production of cytokines and chemokines and 2) induction of reactive oxidative species(ROS) and nitric oxide (NO). PUBLIC HEALTH RELEVANCE: Studies in this proposal will focus on assaying the extent by which opioids and HIV enhances the susceptibility of HCV infection in human hepatocytes in particular, to proinflammatory cytokine tumor necrosis factor-alpha (TNF-1) and we will investigate the mechanisms by which opiates and HIV affect viral replication and toxicity in HCV infected hepatocytes.

描述（由申请人提供）：在注射吸毒者（IDU）中，人类免疫缺陷病毒（HIV）和丙型肝炎病毒（HCV）是最常传播的两种血源性病原体。在美国，约 25% 的 HIV 感染者同时感染丙型肝炎病毒 (HCV)，而通过注射吸毒感染 HIV 的人中 HCV 感染率接近 90%。尽管HCV在HIV疾病进展中的作用尚不清楚，但与HIV感染的合并感染与慢性丙型肝炎向肝硬化和终末期肝病的加速进展有关。 HIV-1 合并感染者肝病进展加快和 HCV 病毒血症增加的机制尚不完全清楚。病毒感染迅速触发细胞内信号事件，导致先天细胞抗病毒状态，而先天免疫的损害可能为持续病毒感染产生有利的微环境。大多数与 HCV 感染相关的肝损伤是由先天性和后天性免疫反应介导的。吗啡是海洛因的主要代谢物，是最常见的阿片类药物，优先激活β-阿片受体（MOR）。长期使用和滥用吗啡已被证明会损害宿主先天免疫反应，包括趋化因子和促炎细胞因子的产生、吞噬作用和中性粒细胞迁移，这可能导致对细菌和病毒感染的易感性增加。吗啡通过下调 IFN-1 介导的先天免疫，有利于肝细胞中的 HCV 复制。趋化因子和促炎细胞因子是免疫反应和炎症过程的重要介质。更具体地说，促炎细胞因子肿瘤坏死因子-1 (TNF-1) 在许多病理生理状态下的肝细胞损伤和细胞死亡中发挥着不可或缺的作用，例如毒素、缺血/再灌注和肝炎病毒引起的肝损伤。此外，据推测，吗啡引起的氧化损伤导致了小鼠和海洛因滥用者实验中显示的肝病和肝毒性的全身表现。 MOR 的激活可以引发活性氧 (ROS) 的产生增加和细胞凋亡。使用最近建立的体外 HCV 感染系统，我们将测试阿片类药物通过破坏肝细胞对 HCV 和 HIV 的反应而导致 HCV 疾病进展的假设，方法是：1) 增加细胞因子和趋化因子的产生，2) 诱导活性氧化物质（ ROS）和一氧化氮（NO）。公共健康相关性：本提案中的研究将侧重于测定阿片类药物和 HIV 在多大程度上增强了人类肝细胞中 HCV 感染的易感性，特别是对促炎细胞因子肿瘤坏死因子-α (TNF-1) 的易感性，我们将研究其机制阿片类药物和 HIV 会影响 HCV 感染的肝细胞中的病毒复制和毒性。