The Role of NOX2 in Liver Fibrosis

描述(由申请人提供)： 肝纤维化是一个复杂的过程，它包括一系列事件，包括炎症细胞的渗透和产生基质的间充质细胞的增殖，以及细胞外基质(ECM)成分的增加，包括I型胶原。肝纤维化过程的中心是肝星状细胞(HSC)。最近我们发现，HSC吞噬死亡肝细胞中的凋亡小体(AB)，从而诱导NADPH氧化酶(NOX)激活，从而产生超氧化物，并释放到细胞内和细胞内环境中。细胞内的超氧化物随后诱导前胶原a1(I)表达上调，从而促进纤维化过程。HSC的吞噬作用可能是一种常见的、普遍的导致纤维化的途径，与肝病的病因无关，将慢性肝损伤与肝细胞凋亡联系起来，清除AB并导致瘢痕形成。由于NOX激活似乎是诱导HSC激活的关键因素，并且吞噬细胞中的NOX(NOX2)是否在吞噬中起作用尚不清楚，我们的假设是AB吞噬特异性地导致NOX2激活，并通过RAC-GTP酶激活信号通路，导致HSC的运动和激活增加。这项提议的具体目的将是回答这一假设产生的两个关键问题： 1.NOX2是否参与了HSC中AB的吞噬作用？和 2.PS是否与其受体(PS-R)结合，进而吞噬AB，诱导NOX2及其下游信号通路？ 在这项建议中，我们开发了新的调查领域，这些领域是原始K08申请中描述的特定目标的自然延伸，并基于K08拨款中描述的研究得出的数据。这些信号事件可能代表了肝纤维化的共同途径，与病因无关，这一事实加强了研究所提出的信号事件的重要性。

DESCRIPTION (provided by applicant): Liver fibrogenesis is a complex process which comprises of a sequence of events including inflammatory cell infiltration and proliferation of matrix-producing mesenchymal cells, with an increased accumulation of the extracellular matrix (ECM) components, including type I collagen. At the center of the fibrogenic process are the hepatic stellate cells (HSC). Recently we have shown that HSC phagocytose apoptotic bodies (AB) from dying hepatocytes and this induces NADPH oxidase (NOX) activation and resulting superoxide production and release both into the intracellular and intracellular milieu. Intracellular superoxide then induces procollagen a 1(I) upregulation, thereby contributing to the fibrogenic process. Phagocytosis by HSC is likely to be a common, universal pathway leading to fibrosis independent of the etiology of the liver disease, linking chronic liver injury with apoptosis of hepatocytes to clearance of AB with resulting scar formation. As NOX activation appears to be a critical element in inducing HSC activation, and it is unknown whether the phagocytic NOX (NOX2) plays role in engulfment, our HYPOTHESIS is that AB engulfment leads specifically to NOX2 activation, and that this via the Rac-GTPase activates signaling pathways, leading to increased motility and activation of HSC. The SPECIFIC AIMS of this proposal will be answering two key questions generated by this hypothesis: 1. Is NOX2 playing a role in the phagocytosis of AB in HSC? And 2. Does PS binding to its receptor (PS-R) on HSC, and the subsequent engulfment of AB, induce NOX2 and downstream signaling pathways? In this proposal we develop new areas of investigation that are the natural extension of the specific aims described in the original K08 application, and based on data derived from the studies described in the K08 grant. The importance of studying the proposed signaling events is enhanced by the fact that these likely represent common pathways in liver fibrosis, independent of etiology.