Viral, T Cell, and Cytokine Determinants of Hepatic Stellate Cell Activation

肝星状细胞激活的病毒、T 细胞和细胞因子决定因素

• 批准号: 7575790
• 负责人: DETLEF SCHUPPAN
• 金额: $ 11.02万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7575790
• 关键词: Biological Models; CD8B1 gene; Cell Line; Cells; Chronic; Chronic Hepatitis C; Cirrhosis; Conditioned Culture Media; Deposition; Development; Disease Progression; Effector Cell; Environment; Europe; Extracellular Matrix; Factor V; Fatty Liver; Genotype; Hepatic Stellate Cell; Hepatitis C; Hepatitis C virus; Hepatocyte; Immune response; Immune system; Infection; Inflammatory; Lead; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Maintenance; Malignant neoplasm of liver; Morbidity - disease rate; Mutation; Myofibroblast; Oxidative Stress; Pathway interactions; Patients; Platelet Factor 4; Play; Process; Replicon; Role; Source; Stimulus; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transforming Growth Factors; Variant; Viral; Viral hepatitis; cofactor; cytokine; extracellular; fibrogenesis; human TGFB1 protein; lipid metabolism; mortality; novel; release factor; response

Chronic hepatitis C virus (HCV) infection has become a major cause of liver related morbidity and mortality in the USA and Europe. Progression of chronic hepatitis C to advanced liver fibrosis and finally cirrhosis is the key predictor of liver failure and the development of primary liver cancer. However, cirrhosis develops in only 20-30% of patients after a mean of 20 years of infection, while others progress more slowly or not at all. Hepatic stellate cells and myofibroblasts, the effector cells of liver fibrosis that are responsible for excess deposition of extracellular matrix components during progression, seem to respond uniformly to fibrogenic stimuli. On the contrary, HCV infected hepatocytes and the host's immune response to HCV appear to be major factors that determine the activation state of hepatic stellate cells and myofibroblasts (collectively termed hepatic stellate cells), most likely via release of profibrogenic factors. In addition, viral genotype and variants (quasispecies) may indirectly (via interaction with the immune system) or directly (via alterations within the infected hepatocytes) stimulate hepatic stellate cell activation and thus fibrogenesis and progression. Furthermore, the mechanistic role of well established cofactors of progression in HCV liver disease, such as hepatic steatosis and enhanced oxidative stress is largely unexplored. To mimic the extracellular environment of hepatic stellate cells, we will use conditioned media from a spectrum of HCV replicating hepatocytic cell lines and from CD4+, CD8+ and NK T cell subsets derived from slow and rapid progressor patients to test the hypothesis that 1. hepatocytic cell lines with replicating HCV release profibrogenic factors that drive activation of hepatic stellate cells, and that a major profibrogenic factor thus released is TGFbeta1. 2. different HCV genotypes (type 1b vs. 2b) and certain quasispecies, defined as mutations in sequence regions of importance, namely in Core, NS4B and NS5A, elicit different levels of profibrogenic factors in the replicon cells or in Core, NS4B/NS5A transfected hepatocytic cells. 3. HCV induced hepatocyte alterations in lipid metabolism and oxidative stress lead to enhanced release of TGF-beta1 and other profibrogenic factors. 4. the cytokine profile released by key inflammatory cells in chronic HCV infection (CD4+, CD8+ and NK T cells) is more fibrogenic in patients with rapid vs. slow progression, and identify the key fibrogenic factors released by these T cell subsets. It is expected that a better understanding of the HCV-induced fibrogenic response in the liver and its cooperation or interaction with other extrinsic and intrinsic profibrogenic triggers and pathways will lead to a better understanding of HCV liver disease progression and to novel antifibrotic treatments tailored to chronic hepatitis C.

慢性丙型肝炎病毒（HCV）感染已成为美国和欧洲相关的发病率和死亡率的主要原因。慢性丙型肝炎对晚期肝纤维化的进展，最后是肝硬化是肝衰竭和原发性肝癌发展的关键预测因子。然而，在平均20年感染后，肝硬化仅在20-30％的患者中发展，而其他患者的进展则更慢。肝星状细胞和肌纤维细胞，肝纤维化的效应细胞，导致进展过程中细胞外基质成分的过量沉积，似乎对纤维基因均无反应 刺激。相反，HCV感染了肝细胞，宿主对HCV的免疫反应似乎是决定肝星状细胞和肌纤维细胞的激活状态（集体称为肝星状细胞）的主要因素，这很可能是通过释放的成能力因素的释放。此外，病毒基因型和变体（准特性）可能会间接（通过与免疫系统相互作用）或直接（通过感染肝细胞内的改变）刺激肝星细胞的激活，从而刺激纤维化和进展。此外，在HCV肝病中，良好的进展辅助因子（例如肝脂肪变性和增强的氧化应激）的机理作用在很大程度上没有探索。为了模仿肝星状细胞的细胞外环境，我们将使用来自HCV复制肝细胞系的条件培养基以及CD4+，CD4+和NK T细胞子集从缓慢和快速进步的患者中得出的，以测试1。肝细胞细胞的假设。具有复制HCV释放能元因子的线，驱动肝星细胞的激活，以及 因此，释放的主要能力因子是TGFBETA1。 2。不同的HCV基因型（1B型vs. 2b）和某些准特性，被定义为重要性序列区域的突变，即在Core，NS4B和NS5A中引起复制细胞中的不同水平的纯果因子，NS4B/NS5A/NS5A/NS5A。转染肝细胞。 3。HCV诱导脂质代谢和氧化应激的肝细胞改变导致TGF-BETA1和其他纤维化因子的释放增强。 4。在慢性HCV感染（CD4+，CD8+和NK T细胞）中，关键炎症细胞释放的细胞因子谱在快速进展与缓慢进展的患者中更具纤维化，并识别这些T细胞群释放的关键纤维化因子。 可以预期，更好地了解肝脏中HCV诱导的纤维化反应，以及与其他外部和内在的和固有的纤维纤维化触发触发和途径的合作或相互作用，将使人们更好地了解HCV肝脏疾病的进展，以及针对针对慢性量身定制的新型抗纤维化处理乙型肝炎。