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（由申请人提供）：肝纤维发生是各种慢性毒性刺激引起的复杂伤口治疗过程。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中纤维化活性之间的直接联系。在肝纤维发生的中心是肝星状细胞，通过吞噬肝细胞的凋亡体诱导纤维化信号通路和产生细胞外基质。 NADPH氧化酶（NOX）的激活是吞噬作用后诱导纤维化活性的关键步骤。因此，我们的假设是HSC中用超氧化物产生的NOX2激活是肝纤维发生过程中的关键事件。为了解决这一假设，我们的具体目的是研究NOX2激活可能起关键作用的以下区域：1。NOX2增加HSC的HSC吞噬活性。HSC2。吞噬作用和NOX2激活诱导纤维源信号通路3。吞噬和NOX2激活诱导肝纤维化引起肝纤维化。该提案发出的数据将有助于定义HSC中慢性肝损伤，吞噬作用和NOX2激活引起的肝细胞凋亡之间的机械联系，以及由此产生的氧化损伤和纤维源反应。此外，拟议的研究将产生有关HSC在纤维发生过程中早期激活的重要数据，这些数据可能转化为设计理性的治疗方法，以防止纤维化进展。 公共卫生相关性：肝硬化是全球发病率和死亡率的主要原因。产生的细胞外基质的产生是纤维化过程中的中心事件。但是，发生这种情况的机制尚未完全理解。我们先前已经表明，肝细胞的星状细胞吞噬细胞凋亡人物，这直接通过激活NADPH氧化酶（NOX）而直接诱导其纤维化激活。在这里，我们建议NOX2是肝纤维发生中的关键酶，其在星状细胞中的激活会导致纤维化基因的上调。源自提出的实验的成功完成的信息有可能发展为预防和治疗肝纤维化的策略。