Phagocytosis and NOX2 in Liver Fibrogenesis

描述(申请人提供)：肝纤维化是由各种慢性毒性刺激引起的一个复杂的伤口愈合过程。肝细胞凋亡是肝脏慢性炎症的一个主要特征，最近我们证实了肝细胞凋亡与肝脏纤维化活动之间的直接联系。肝纤维化的中心是肝星状细胞，它通过吞噬肝细胞的凋亡体，诱导肝纤维化的信号通路和细胞外基质的产生。NADPH氧化酶(NOX)的激活是诱导吞噬后纤维化活性的关键步骤。因此，我们的假设是，在HSC中NOX2的激活和超氧化物的产生是肝纤维化过程中的一个关键事件。针对这一假说，我们的具体目标是研究NOX2激活可能在以下方面发挥关键作用：1.NOX2增加HSC的吞噬活性；2.吞噬和NOX2激活诱导纤维化信号通路；3.吞噬和NOX2激活在体内诱导肝纤维化。这一建议的数据将有助于确定慢性肝损伤导致的肝细胞凋亡、HSC的吞噬作用和NOX2激活，以及由此导致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HSC在纤维化形成过程中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防止纤维化的进展。 公共卫生相关性：肝硬变是世界范围内发病率和死亡率的主要原因。肝星状细胞的活化以及由此产生的细胞外基质是纤维化过程中的中心事件；然而，其发生的机制尚不完全清楚。我们先前已经证明，星状细胞吞噬肝细胞中的凋亡小体，这直接通过激活NADPH氧化酶(NOX)诱导其纤维化激活。在这里，我们认为NOX2是肝纤维化形成的关键酶，它在星状细胞中的激活导致促纤维化基因的上调。来自拟议实验的成功完成的信息有可能发展成预防和治疗肝纤维化的策略。

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.