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Evolving challenges in hepatic fibrosis
Scott L. Friedman
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 progressin 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 apoptosisand 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.
Friedman, S. L. Nat. Rev. Gastroenterol. Hepatol. 7, 425436 (2010); published online 29 June 2010; http://www.nature.com/doifinder/10.1038/nrgastro.2010.97
Web End =doi:10.1038/nrgastro.2010.97
Introduction
The field of hepatic fibrosis enjoys remarkable vitalitya PubMed search with the keywords hepatic fibrosis or hepatic stellate cell reveals that there were approximately 3,304 publications on the topic in 2009 alone, and 15,377 publications over the past 5 years. A prior review of the topic in this journal in 20041 emphasized the emerging mechanisms of the disease and their therapeutic implications, focusing on the role of the hepatic stellate cell (HSC) as the key fibrogenic element in response to chronic liver injury. More recent advances in the cellular and molecular biology of the fibrotic wound healing response have moved into surprising new frontiers, including stem cells, immune and apoptotic signaling, and epigenetics. Complementing these advances is further proof that the liver is uniquely resilient, with evidence that cirrhosis has regressed in a growing number of patients whose underlying liver disease has been treated effectively.
Progress could not arrive a moment too soon. A recent Institute of...