Liver fibrosis, a reversible wound-healing response to chronic cellular injury, reflects a balance between liver repair and progressive substitution of the liver parenchyma by scar tissue. Complex mechanisms that underlie liver fibrogenesis are summarized to provide the basis for generating targeted therapies to reverse fibrogenesis and improve the outcomes of patients with chronic liver disease. This minireview presents some pathophysiological aspects of liver fibrosis as a dynamic process and elucidates matrix metalloproteinases (MMPs) and their role within as well as beyond matrix degradation. Open questions remain, whether inhibition of fibrogenesis or induction of fibrolysis is the key mechanism to resolve fibrosis. And a point of principle might be whether regeneration of liver cirrhosis is possible. Will we ever cure fibrosis?

^* Diese Autoren sind gleichberechtigt. AG-Leiter 3 – 17 in alphabetischer Reihenfolge. ^# Für die Autoren des DGVS Leitlinien-Komitees.

Tissue inhibitor of metalloproteinases‐1 (TIMP‐1) plays a crucial role in the pathogenesis of hepatic fibrosis and thus may represent an important therapeutic target in the design of anti‐fibrotic strategies for chronic liver disease. We present an innovative therapy based on the assignment of inactivated enzymes acting as scavengers for TIMP‐1. Hepatic fibrosis was induced in BALB/c mice by repetitive intraperitoneal CCl ₄ injection. The animals were treated with proteolytic inactive matrix metalloproteinase‐9 mutants (E402Q, H401A, E402H/H411E) using adenovirus‐mediated gene transfer. Application of these MMP‐9 mutants inhibited fibrogenesis, which was indicated by decreasing portal and periportal accumulation of collagen. Total hydroxyproline of liver tissue, the morphometric stage of fibrosis as well as mRNA expression of marker proteins for hepatic fibrosis in livers of E402Qand H401A‐treated mice were significantly reduced. MMP‐9 mutants suppressed transdifferentiation of hepatic stellate cells to the myofibroblast like phenotype in vitro and in vivo. Moreover, adenoviral application of the mutants MMP‐9‐H401A and ‐E402Q led to increased apoptosis of activated hepatic stellate cells, thought to be the main promoters of hepatic fibrosis. Application of MMP‐9 mutants as TIMP‐1 scavengers may provide a new therapeutic strategy for hepatic fibrosis.—Roderfeld, M., Weiskirchen, R., Wagner, S., Berres, M.‐L., Henkel, C., Grötzinger, J., Gressner, A. M., Matern, S., Roeb, E. Inhibition of hepatic fibrogenesis by matrix metalloproteinase‐9 mutants in mice. FASEB J. 20, 444–454 (2006)

Matrix metalloproteinases (MMPs) are responsible for the turnover and degradation of extracellular matrix. They play a crucial role in the growth and

Nonalcoholic fatty liver disease (NAFLD) includes nonalcoholic fatty liver (NAFL), nonalcoholic steato hepatitis (NASH) and NASH cirrhosis. NAFLD is the leading cause of liver diseases in the Western world (Central Europe, United States). The NAFLD incidence increases because of increasing type 2 diabetes and obesity. This article reviews the scientific findings of epidemiology, diagnostic, and therapeutic management of NAFLD. Lifestyle modifications (low-caloric Mediterranean diet and exercise training) to reduce weight are a major factor in the treatment of NAFLD.Pharmacological therapies may be useful in patients with NASH and fibrosis as well as nonresponders to lifestyle modifications. Currently, however, no pharmacological substances are approved for the indication NASH.