Abstract
Continued elucidation of the mechanisms of hepatic fibrosis has yielded a comprehensive and nuanced portrait of fibrosis progression and regression. The paradigm of hepatic stellate cell (HSC) activation remains the foundation for defining events in hepatic fibrosis and has been complemented by progress in a number of new areas. Cellular sources of extracellular matrix beyond HSCs have been identified. In addition, the role of chemokine, adipokine, neuroendocrine, angiogenic and NAPDH oxidase signaling in the pathogenesis of hepatic fibrosis has been uncovered, as has the contribution of extracellular matrix stiffness to fibrogenesis. There is also increased awareness of the contribution of innate immunity and greater understanding of the complexity of gene regulation in HSCs and myofibroblasts. Finally, both apoptosis and senescence have been recognized as orchestrated programs that eliminate fibrogenic cells during resolution of liver fibrosis. Ironically, the progress that has been made has highlighted the growing disparity between advances in the experimental setting and their translation into new diagnostic tools and treatments. As a result, focus is shifting towards overcoming key translational challenges in order to accelerate the development of new therapies for patients with chronic liver disease.
Key Points
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Progress in defining the cellular and molecular basis of hepatic fibrosis has brought us to a juncture where translation of these discoveries into diagnostic tools and treatments is nearing reality
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Novel therapeutic targets continue to be unearthed by new discoveries, including the emergence of the hepatic stellate cell (HSC) as an immunoregulatory cell type
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HSCs are also now known to participate in adipokine, angiogenic and neuroendocrine signaling, interact with other resident cell types and be regulated by epigenetic and transcriptional mediators
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Finding better noninvasive markers of fibrogenic activity and disease progression is a high priority in order to accelerate progress in developing antifibrotic drugs
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Genetic markers that predict fibrosis progression risk, combined with new paradigms to stratify the risk of decompensation among patients with cirrhosis, should improve clinical trial design quality and patient selection for antifibrotic therapies
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Acknowledgements
Work in the author's laboratory is supported by NIH grants RO1DK37340, RO1DK56621, P20AA017067 and 1K05AA018408-01. This article highlights primarily recent studies and review articles of general interest to the readership. As a result many outstanding publications in the field could not be cited because of space constraints.
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Scott L. Friedman is a consultant for Abbott, Amgen, Axcan Pharma, Human Genome Sciences, MDRNA, Onyx Pharmaceuticals, Salix Pharmaceuticals, Sanofi Aventis and Siemens Diagnostics (each less than US$5,000 per annum). He has stock ownership/equity and is a consultant for Angion Biomedica, Conatus Pharmaceuticals, Exalenz and Intercept Pharmaceuticals (each less than US$10,000 and less than 5%). He has restricted grants and contracts with Celera (to study the mechanisms linking fibrosis risk SNPs to pathogenesis) and Bayer/Onyx Pharmaceuticals (to study antifibrotic activity of sorafenib in hepatic fibrosis). He also holds US patents on noninvasive agents for diagnosis and prognosis of the progression of fibrosis (US Patent no. 6,264,949 B1) and KLF6, a novel growth inhibitory and tumor suppressor gene (US Patent no. US2005/0181374), and has four other US patents pending that relate to hepatic fibrosis and/or hepatocellular carcinoma.
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Friedman, S. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 7, 425–436 (2010). https://doi.org/10.1038/nrgastro.2010.97
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DOI: https://doi.org/10.1038/nrgastro.2010.97
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