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: 7686014
• 负责人: NAZIRA EL-HAGE
• 金额: $ 14.94万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686014
• 关键词: Affect; Antioxidants; Antiviral Agents; Apoptosis; Biological Assay; Blood-Borne Pathogens; Cell Death; Cells; Chronic; Chronic Hepatitis C; Cirrhosis; Communicable Diseases; 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; Morbidity - disease rate; 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（IDUs）中，人类免疫缺陷病毒（HIV）和丙型肝炎病毒（HCV）是两种最常见的经血液传播的病原体。在美国，约25%的HIV感染者也感染丙型肝炎病毒（HCV），而通过注射吸毒获得HIV的人中HCV感染的发病率接近90%。虽然HCV在HIV疾病进展中的作用尚不清楚，但与HIV感染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。在HIV-1合并感染的个体中，肝脏疾病进展更快和HCV病毒血症增加的机制尚未完全了解。病毒感染迅速触发细胞内信号传导事件，导致先天性细胞抗病毒状态，并且对先天免疫的损害可产生持续病毒感染的有利微环境。大多数与HCV感染相关的肝损伤是由先天性和获得性免疫反应介导的。吗啡是海洛因的主要代谢物，是最常见的阿片类药物，并优先激活α-阿片受体（莫尔）。研究表明，长期使用和滥用吗啡会损害宿主的先天免疫反应，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，从而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，促进HCV在肝细胞中的复制.趋化因子和促炎细胞因子是免疫应答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如毒素、缺血/再灌注和肝炎病毒引起的肝损伤中的肝细胞损伤和细胞死亡中起着不可或缺的作用。此外，在小鼠和海洛因滥用者中，吗啡诱导的氧化损伤被假设为导致肝脏疾病和肝毒性的太多全身表现。莫尔的激活可触发活性氧（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，我们将检验阿片类药物通过1）增加细胞因子和趋化因子的产生和2）诱导活性氧化物质（ROS）和一氧化氮（NO）破坏肝细胞对HCV和HIV的反应而促进HCV疾病进展的假设。公共卫生相关性：本提案中的研究将侧重于分析阿片类药物和HIV在何种程度上增强了人肝细胞中HCV感染对促炎细胞因子肿瘤坏死因子-α（TNF-1）的易感性，我们将研究阿片类药物和HIV影响HCV感染肝细胞中病毒复制和毒性的机制。