Clinical evidence for the regression of liver fibrosis.

Fibrosis is a common pathological process for the majority of liver diseases which in a significant minority of patients leads to end-stage cirrhosis and/or hepatocellular carcinoma. Data emerging from small rodent models of chronic liver disease have demonstrated that fibrotic extracellular matrix can be remodelled and near-normal hepatic architecture regenerated upon cessation of injury. Moreover, regression of liver fibrosis in these model systems can be stimulated with drugs that target the activities of fibrogenic hepatic stellate cells. These findings are exciting as they suggest that established fibrosis is susceptible to regression and possibly even reversion. Alongside these experimental studies is a growing body of clinical data that suggest regression of fibrosis may also occur in liver disease patients for whom an effective treatment is available for their underlying liver injury. This paper provides an up-to-date review of the currently available clinical data and also considers technical caveats that highlight the need for caution in establishing a new dogma that human liver fibrosis is reversible.

The NF-κB subunit c-Rel stimulates cardiac hypertrophy and fibrosis.

Cardiac remodeling and hypertrophy are the pathological consequences of cardiovascular disease and are correlated with its associated mortality. Activity of the transcription factor NF-κB is increased in the diseased heart; however, our present understanding of how the individual subunits contribute to cardiovascular disease is limited. We assign a new role for the c-Rel subunit as a stimulator of cardiac hypertrophy and fibrosis. We discovered that c-Rel-deficient mice have smaller hearts at birth, as well as during adulthood, and are protected from developing cardiac hypertrophy and fibrosis after chronic angiotensin infusion. Results of both gene expression and cross-linked chromatin immunoprecipitation assay analyses identified transcriptional activators of hypertrophy, myocyte enhancer family, Gata4, and Tbx proteins as Rel gene targets. We suggest that the p50 subunit could limit the prohypertrophic actions of c-Rel in the normal heart, because p50 overexpression in H9c2 cells repressed c-Rel levels and the absence of cardiac p50 was associated with increases in both c-Rel levels and cardiac hypertrophy. We report for the first time that c-Rel is highly expressed and confined to the nuclei of diseased adult human hearts but is restricted to the cytoplasm of normal cardiac tissues. We conclude that c-Rel-dependent signaling is critical for both cardiac remodeling and hypertrophy. Targeting its activities could offer a novel therapeutic strategy to limit the effects of cardiac disease.