Hepatic fibrosis: from bench to bedside.
Antifibrotic therapies are preferentially targeted to the activated mesenchymal cells in the liver that synthesize an excess of matrix proteins and resemble the myofibroblasts of healing wounds. These cells derive from normally quiescent hepatic stellate cells and (myo-) fibroblasts. Their activation is triggered and maintained by several fibrogenic modulators and cytokines, but also by mechanical stress. Whereas many agents inhibit stellate cell/myofibroblast proliferation and collagen synthesis in vitro, only few of them are tolerable or effective in suitable animal models in vivo. An antifibrotic effect was demonstrated for silymarin, a defined mixture of flavonoids, sho-saiko-to which contains the related compound baicalein, for halofuginone, another plant-derived agent, for the phosphodiesterase inhibitor pentoxifylline and for LU135252, an oral inhibitor of the endothelin-A-receptor. The retrospective finding that interferon-alpha therapy for hepatitis C may halt or even reverse fibrosis, has to be confirmed in prospective randomized trials. Strategies to inhibit the profibrogenic cytokines transforming growth factor (TGF)-beta or connective tissue growth factor (e.g. by soluble decoy receptors) are evolving, but have not been convincing yet. Drug targeting to the fibrogenic liver cells is now possible by use of cyclic peptides that bind to receptors which are specifically up-regulated on activated stellate cells, for example those for platelet-derived growth factors or collagen type VI. In addition, blockade of such activation receptors can induce stress-relaxation which reverts the fibrogenic cells to a fibrolytic, collagen degrading phenotype. Combined with the evolving validation of serological markers of fibrogenesis and fibrolysis an effective and individualized treatment of liver fibrosis can be anticipated.
Schuppan
Detlef
D
Department of Medicine I, Division of Gastroenterology, Hepatology and Infectiology, University of Erlangen-Nuernberg, Germany. detlef.schuppan@med1.med.uni-erlangen.de
Popov
Yury
Y
Porov
Yury
Y
D000933:Antifibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000209:etiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D000933:Antifibrinolytic Agents; D016207:Cytokines