Mechanisms of Progression and Regression of Liver Fibrosis

Summary

There have been major advances in our understanding of the molecular and cell biology of liver fibrosis. The hepatic stellate cell (HSC) orchestrates most of the important events in this pathological process and is pivotal to both the progression and the regression of liver fibrosis. After liver injury, HSCs become activated to a profibrogenic myofibroblastic phenotype and can regulate net deposition of collagens and other matrix proteins in the liver. This is achieved not only by regulation of matrix protein synthesis but also by expression of matrix-degrading metalloproteinases and their inhibitors. These events can be modeled in cell culture, and this methodology, combined with studies of fibrotic models and human liver disease, has led to rapid progress in the field. Recent advances include improved understanding of the molecular mechanisms of HSC activation and the persistence of the activated phenotype. There is also increasing evidence for reversibility of liver fibrosis in models of liver injury and in human liver disease, with clear experimental and observational evidence that regression is mediated by a combination of apoptosis of activated HSCs and increased matrix degradation. In combination, these studies have raised the prospect of the development of effective antifibrotic therapeutic agents for use in chronic liver disease in humans.