Phagocytosis and NOX2 in Liver Fibrogenesis

描述（申请人提供）：肝纤维化是一个复杂的伤口愈合过程，由各种慢性毒性刺激引起。肝细胞凋亡是肝脏慢性炎症的主要特征，最近我们已经证明肝细胞凋亡与肝脏纤维化活性之间存在直接联系。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的激活与超氧化物的产生是肝纤维化过程中的一个关键事件。为了解决这一假设，我们的具体目标将是研究NOX2激活可能发挥关键作用的以下领域：NOX2增加HSC吞噬活性。吞噬作用和NOX2激活诱导纤维化信号通路体内吞噬作用和NOX2激活诱导肝纤维化。该提案的数据将有助于确定HSC中慢性肝损伤、吞噬和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，拟议的研究将获得关于纤维形成过程中HSC早期活化的重要数据，这可能转化为设计合理的治疗方法来预防纤维化的进展。

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.