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Gut doi:10.1136/gutjnl-2014-306842
Recent advances in basic science
Pathobiology of liver fibrosis: a translational success story
Youngmin A Lee,
Michael C Wallace,
Scott L Friedman
+ Author Affiliations
Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
Correspondence to Scott L Friedman, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave., Room 11-70C, Box 1123, New York, NY 10029-6574, USA; [email protected]
Received 16 December 2014
Revised 6 January 2015
Accepted 7 January 2015
Published Online First 13 February 2015
Abstract
Reversibility of hepatic fibrosis and cirrhosis following antiviral therapy for hepatitis B or C has advanced the prospect of developing antifibrotic therapies for patients with chronic liver diseases, especially non-alcoholic steatohepatitis. Mechanisms of fibrosis have focused on hepatic stellate cells, which become fibrogenic myofibroblasts during injury through ‘activation’, and are at the nexus of efforts to define novel drug targets. Recent studies have clarified pathways of stellate cell gene regulation and epigenetics, emerging pathways of fibrosis regression through the recruitment and amplification of fibrolytic macrophages, nuanced responses of discrete inflammatory cell subsets and the identification of the ‘ductular reaction’ as a marker of severe injury and repair. Based on our expanded knowledge of fibrosis pathogenesis, attention is now directed towards strategies for antifibrotic therapies and regulatory challenges for conducting clinical trials with these agents. New therapies are attempting to: 1) Control or cure the primary disease or reduce tissue injury; 2) Target receptor-ligand interactions and intracellular signaling; 3) Inhibit fibrogenesis; and 4) Promote resolution of fibrosis. Progress is urgently needed in validating non-invasive markers of fibrosis progression and regression that can supplant biopsy and shorten the duration of clinical trials. Both scientific and clinical challenges remain, however the past three decades of steady progress in understanding liver fibrosis have contributed to an emerging translational success story, with realistic hopes for antifibrotic therapies to treat patients with chronic liver disease in the near future.
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发表于 2015-2-14 21:47