Additionally, enteric viruses are able to survive in the environment under a wide pH range and for extended time periods

MIT Alliance Computational and Systems Biology Flagship Project funding; and Mechanobiology Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. E-mail: [email protected] Introduction Liver fibrosis, a disease 15516710” of excessive extracellular matrix accumulation, is a common downstream response to repeated liver injury, caused by factors such as hepatitis B or C virus infection, excessive alcohol consumption, non-alcoholic steatohepatitis, autoimmune hepatitis, or drugs and toxins such as azathioprine, D-galactosamine or low doses of paracetamol. In current clinical practice, the most effective anti-fibrotic treatment is indirect: to target the underlying cause of injury, as removal of primary insults may lead to spontaneous regression of fibrosis. For example, lamivudine, which blocks hepatitis B virus replication, can result in fibrosis resolution. However, fully activated hepatic stellate cells, besides being a major source of fibrotic ECM, also secrete a broad range of chemokines and cytokines for self-perpetuating fibrosis in the absence of primary insults. As a result, indirect treatment by removing the underlying irritant is not effective in a significant population of liver fibrosis patients. Current drug discovery efforts for direct anti-fibrotic therapies have primarily GS-4059 targeted activated HSCs. Over recent years, the focus in drug discovery research has shifted from 15516710” cell-free approaches based on molecular targets, to cell-based systemsbiology based approaches, in an effort to increase success rates and reduce the overhead costs of drug development. Since multiple complex pathways are involved in fibrogenesis, it is important to study the anti-fibrotic effects of a drug in the cellular context. Several high-throughput in vitro screenings have been performed November 2011 | Volume 6 | Issue 11 | e26230 Ranking Anti-Fibrotic Drugs previously on HSCs or fibroblast cells. Xu et. al. established a quantitative screening platform based on TGF-b1 dependent fibroblast nodule formation. Using this system, 8 out of 21 herbal extracts were found to have anti-fibrotic activities. In other studies, HSC proliferation and apoptosis were used to assess the direct effects of drugs on HSC. Collagen expression is another indicator commonly used in high-throughput systems. These studies together with conventional low-throughput in vitro and in vivo studies have identified a diverse group of positive chemicals. The most promising ones, such as losartan, pioglitazone and Fuzheng Huayu tablets, have entered phase IV clinical trials. Despite numerous efforts in anti-fibrotic drug discovery, there is no anti-fibrotic drug approved by the U.S. Food and Drug Administration. Many candidate drugs for fibrosis have failed in preclinical or clinical trials. One of the reasons is that in vitro data have poor correlation with in vivo drug effects due to the complicated pathophysiological background of hepatic fibrogenesis. As a result, drugs with high in vitro efficacies based on simple biochemical assays may fail to produce significant in vivo effects. Despite the different levels of complexity between the in vitro and in vivo systems, previous studies from other fields such as drug dissolution, have demonstrated that optimized design of in vitro systems can result in better correlation with in vivo