Phagocytosis and NOX2 in Liver Fibrogenesis

肝纤维形成中的吞噬作用和 NOX2

• 批准号: 8045365
• 负责人: Natalie J. Torok
• 金额: $ 31.15万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-20 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045365
• 关键词: Address; Animals; Apoptosis; Apoptotic; Area; Cell membrane; Cells; Chronic; Chronic Granulomatous Disease; Collagen; Complex; Data; Deposition; Enzymes; Event; Extracellular Matrix; Extracellular Matrix Proteins; Fibrosis; Gelatinase A; Genes; Hepatic; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatocyte; Indium; Inflammation; Inflammatory; Injury; Injury to Liver; Ligation; Link; Liver; Liver Cirrhosis; Liver Fibrosis; MAPK3 gene; Mediating; Modeling; Morbidity - disease rate; Mus; Mutation; NADP; Oxidases; Pathway interactions; Patients; Peroxides; Phagocytosis; Play; Process; Procollagen; Production; Proteins; Rodent Model; Role; Signal Pathway; Signal Transduction; Stimulus; Superoxides; Testing; Therapeutic; Transforming Growth Factors; Translating; Up-Regulation; Wound Healing; base; bile duct; design; fibrogenesis; in vivo; mortality; novel; oxidative damage; prevent; promoter; public health relevance; research study; response; stellate cell

DESCRIPTION (provided by applicant): Liver fibrogenesis is a complex wound-healing process elicited by various chronic toxic stimuli. Hepatocyte apoptosis is a main feature of chronic inflammation in the liver, and recently we have demonstrated a direct link between hepatocyte apoptosis and fibrogenic activity in the liver. At the center of liver fibrogenesis are the hepatic stellate cells, which by phagocytosing apoptotic bodies of hepatocytes induce fibrogenic signaling pathways and production of extracellular matrix. Activation of the NADPH oxidase (NOX) is a crucial step in the induction of the fibrogenic activity following phagocytosis. Thus, our HYPOTHESIS is that NOX2 activation with superoxide production in HSC is a key event during liver fibrogenesis. To address this hypothesis our SPECIFIC AIMS will be to study the following areas where NOX2 activation may play a key role: 1. NOX2 increases HSC phagocytic activity of HSC 2. Phagocytosis and NOX2 activation induce fibrogenic signaling pathways 3. Phagocytosis and NOX2 activation induce liver fibrogenesis in vivo. The data emanating from this proposal will help define the mechanistic links between hepatocyte apoptosis resulting from chronic liver injury, phagocytosis and NOX2 activation in HSC, and the resulting oxidative damage and fibrogenic response. Furthermore, the proposed studies will yield important data on the early activation of HSC during fibrogenesis which may translate into designing rational therapeutic approaches to prevent progression of fibrosis. PUBLIC HEALTH RELEVANCE: Liver cirrhosis is a leading cause of morbidity and mortality worldwide. Hepatic stellate cell activation with the resulting production of extracellular matrix is a central event in the fibrogenic process; however, the mechanism by which this occurs is not fully understood. We have previously shown that stellate cells phagocytose apoptotic bodies from hepatocytes and this directly induces their fibrogenic activation via activation of the NADPH oxidase (NOX). Here we propose that NOX2 is a key enzyme in liver fibrogenesis and its activation in stellate cells leads to upregulation of profibrogenic genes. Information originating from the successful completion of the proposed experiments has the potential to be developed into strategies to prevent and treat liver fibrosis.

描述（申请人提供）：肝纤维化是由各种慢性毒性刺激引起的复杂的伤口愈合过程。肝细胞凋亡是肝脏慢性炎症的主要特征，最近我们证明了肝细胞凋亡与肝脏纤维化活性之间的直接联系。肝纤维化的核心是肝星状细胞，其通过吞噬肝细胞的凋亡小体诱导纤维化信号通路和细胞外基质的产生。 NADPH 氧化酶 (NOX) 的激活是吞噬作用后诱导纤维形成活性的关键步骤。因此，我们的假设是 HSC 中 NOX2 激活和超氧化物产生是肝纤维形成过程中的关键事件。为了解决这一假设，我们的具体目标将是研究 NOX2 激活可能在以下领域发挥关键作用： 1. NOX2 增加 HSC 的吞噬细胞活性 2. 吞噬作用和 NOX2 激活诱导纤维形成信号通路 3. 吞噬作用和 NOX2 激活诱导体内肝纤维形成。该提案产生的数据将有助于确定慢性肝损伤、HSC 中的吞噬作用和 NOX2 激活导致的肝细胞凋亡与由此产生的氧化损伤和纤维化反应之间的机制联系。此外，拟议的研究将产生关于纤维化过程中 HSC 早期激活的重要数据，这可能转化为设计合理的治疗方法来预防纤维化的进展。 公共卫生相关性：肝硬化是全世界发病和死亡的主要原因。肝星状细胞活化并产生细胞外基质是纤维形成过程中的核心事件。然而，这种现象发生的机制尚不完全清楚。我们之前已经表明，星状细胞吞噬肝细胞的凋亡小体，这通过 NADPH 氧化酶（NOX）的激活直接诱导其纤维化激活。在这里，我们提出 NOX2 是肝纤维发生中的关键酶，其在星状细胞中的激活导致促纤维发生基因的上调。成功完成所提出的实验所产生的信息有可能被开发成预防和治疗肝纤维化的策略。