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）：注射吸毒者（IDU），人类免疫缺陷病毒（HIV）和丙型肝炎病毒（HCV）是最常见的两种血液传播病原体。在美国，大约25％的艾滋病毒感染者也感染了丙型肝炎病毒（HCV），而从注射药物使用的人中获得HIV的人的HCV感染发生率为90％。尽管HCV在HIV疾病进展中的作用尚不清楚，但与HIV感染的共感染与慢性丙型肝炎的加速肝硬化和末期肝病的加速有关。尚未完全了解与HIV-1共同感染​​的个体中肝病和HCV病毒血症增加的更快进展的机制。病毒感染迅速触发细胞内信号传导事件，导致先天的细胞抗病毒状态，对先天免疫的损害可能会产生良好的微环境，以持续使用持续的病毒感染。与HCV感染相关的大多数肝损伤是由先天和获得的免疫反应介导的。吗啡是海洛因的主要代谢产物，是最常见的阿片类药物，优先激活<opio-opio-opiole受体（MOR）。慢性吗啡的使用和滥用已被证明会损害宿主先天免疫反应，包括趋化因子和促炎性细胞因子的产生，吞噬作用和中性粒细胞迁移，这会导致对细菌和病毒感染的敏感性增加。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。趋化因子和促炎性细胞因子是免疫反应和炎症过程的重要介质。更具体地说，在许多病理生理状态（例如毒素，缺血/再生/再灌注和肝炎病毒）中，促炎细胞因子，肿瘤坏死因子1（TNF-1）在肝细胞损伤和细胞死亡中起着不可或缺的作用。此外，假设吗啡诱导的氧化损伤可以在小鼠和海洛因滥用器中实验表明的肝病和肝毒性的系统性表现过多。 MOR的激活会触发活性氧（ROS）和凋亡的产生增加。使用最近建立的体外HCV感染系统，我们将检验以下假设：阿片类药物通过破坏肝细胞对HCV和HIV的反应来促进HCV疾病的进展，通过1）增加细胞因子和趋化因子的产生，趋化因子和2）诱导反应性氧化物种（ROS）和氮氧化物（NO）。公共卫生相关性：该提案中的研究将着重于分析阿片类药物和HIV尤其是人类肝细胞中HCV感染的敏感性，以促进促炎细胞因子肿瘤坏死因子因子-Alpha（TNF-1）的敏感性，并且我们将通过对治疗剂的毒性和HC的毒性进行了调查，并对其进行了促进性的重复，并对其进行了反应效果。