Rationale and targets for antifibrotic therapies

We have made striking progress in our understanding of the biochemistry and cell biology that underlies liver fibrosis and cirrhosis, including the development of strategies and agents to prevent and reverse fibrosis and incipient cirrhosis. However, translation of this knowledge into clinical practice has been hampered by the limitation of many in vitro and in vivo models to confirm mechanisms and to test antifibrotic agents, as well as the lack of sensitive methodologies to quantify the degree of liver fibrosis and the dynamics of fibrosis progression or reversal. Furthermore, while cirrhosis and subsequent decompensation are accepted hard clinical end-points, fibrosis and fibrosis progression alone are merely plausible surrogates for future clinical deterioration. This review focuses on basic mechanisms that underlay liver fibrosis progression and reversal and optimized strategies for preclinical antifibrotic drug development and validation. Therapies include several drugs that are of proven safety for other indications, agents that interfere with major fibrogenic or fibrolytic mechanisms, targeted drug delivery to the fibrogenic liver cells, and their potential combinations with hepatocyte or stem cell replenishment.