Mechanisms of Hepatitis C virus induced hepatocyte injury.

丙型肝炎是一个全球性问题，全世界有超过2%的人感染丙型肝炎。美国人口感染，约1.8亿人。虽然这种疾病可能需要几十年的时间来发展，但大多数慢性感染者最终会出现肝损伤的迹象。在过去的几年里，hcv相关肝衰竭的发病率在英国显著增加，一些研究预测在未来十年中将进一步增加50% - 100%。hcv相关的肝衰竭现在是英国肝移植的主要指标。不幸的是，目前唯一的治疗方法（聚乙二醇干扰素+利巴韦林）是昂贵的，有明显的副作用，而且往往无效。因此，迫切需要新的方法来治疗这种疾病。肝脏的主要功能之一是合成胆汁，胆汁通过胆管和肝脏其他部分之间的极化屏障与血液供应分开。与丙型肝炎病毒感染相关的肝损伤的几种表现包括一定程度的胆道系统衰竭，导致肝脏被胆汁酸损害。HCV进入细胞涉及参与细胞极化的蛋白，特别是紧密连接蛋白claudin1。我们已经证明，HCV感染的细胞具有改变的极性，并表达过量的血管内皮生长因子（VEGF），一种破坏细胞极化的蛋白质。去极化是通过病毒的两种结构成分，包膜蛋白E1和E2介导的，它们将Claudin-1蛋白隔离在细胞内并刺激VEGF的表达。用抑制VEGF活性的抗体治疗HCV感染培养物可消除新一轮HCV感染，为抗病毒干预提供了令人兴奋的新途径。值得注意的是，如果该方法在本研究过程中得到验证，合适的VEGF拮抗剂已经被批准用于治疗各种晚期癌症，我们预计药物开发过程将大大加快。

HCV disease is a global problem, with over 2% of the world?s population infected, some 180 million people. Although the disease may take decades to progress, the majority of chronically infected people will eventually show signs of liver damage. In the last few years the incidence of HCV-associated liver failure has increased considerably in the U.K. and several studies have predicted a further 50 - 100% increase in the next decade. HCV-associated liver failure is now the leading indicator for liver transplantation in the UK. Unfortunately the only current therapy (pegylated interferon + ribavirin) is expensive, has significant side effects and is often ineffective. Hence, there is an urgent need for new approaches to treat this disease.One of the prime functions of the liver is the synthesis of bile, which is kept separate from the blood supply by a polarized barrier between the biliary vessels and the rest of the liver. Several manifestations of liver injury associated with HCV infection involve some degree of failure of this biliary system, leading to the liver being damaged by bile acid. HCV entry into cells involves proteins involved in cell polarization, notably the tight junction protein Claudin?1. We have shown that HCV infected cells have an altered polarity and express excessive quantities of Vascular Endothelial Growth Factor (VEGF), a protein which disrupts cell polarization. Depolarisation is mediated via two structural components of the virus, the envelope proteins E1 and E2, that sequester Claudin-1 protein within the cell and stimulate VEGF expression. Treatment of HCV infected cultures with an antibody that inhibits VEGF activity abrogates new rounds of HCV infection, providing an exciting new avenue for antiviral intervention. It is worth noting that, if this approach is validated during the course of this study, suitable VEGF antagonists are already approved for the treatment of various advanced cancers, and we would anticipate the process of drug development to be considerably accelerated.