Antifibrogenic therapies in chronic HCV infection.
The most common cause of hepatic fibrosis is currently chronic HCV infection, the characteristic feature of which is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which in turn activates hepatic stellate cells (HSCs). HSCs are also regarded as the primary target cells for inflammatory stimuli, and produce extracellular matrix components. It should be noted that transforming growth factor beta (TGF-beta) is a potent fibrogenic cytokine produced by Kupffer cells and HSCs. There are several approaches to inhibit TGF-beta; use of decorin, soluble receptors, and gene therapy approaches. Hepatocyte growth factor (HGF) is a hepatotrophic factor for liver regeneration and seems to suppress hepatic fibrogenesis in animals. HOE 77, Safironil, and S 4682 are inhibitors of prolyl 4-hydroxylase, which is essential for thecollagen formation. Although HOE 77, Safironil, and S 4682 seem to work by inhibiting HSC activation, further studies will be required before their clinical application. alpha-Tocopherol, retinyl palmitate, and silybinin reduce lipid peroxidation and attenuate HSC activation in experimental models. Retinyl palmitate is the main storage type for retinoids in HSCs. Silymarin is extracted from milk thistle, the principle component of which is the silybinin. Unfortunately, they have had mixed effects in human liver diseases. A Japanese herbal medicine Sho-saiko-to functions as a potent antifibrosuppressant via the inhibition of oxidative stress in hepatocytes and HSCs. Its active components are baicalin and baicalein of flavonoids with chemical structures very similar to silybinin. Understanding the basic mechanisms underlying the HCV-mediated fibrogenesis provides valuable information on the search for effective antifibrogenic therapies.
Shimizu
I
I
Second Department of Internal Medicine, Tokushima University School of Medicine, Tokushima, Japan. shimizui@clin.med.tokushima-u.ac.jp
D000975:Antioxidants / Q000627:therapeutic use; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000627:therapeutic use; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D008103:Liver Cirrhosis / Q000188:drug therapy*; D009842:Oligopeptides / Q000627:therapeutic use; D012176:Retinoids / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors
D000975:Antioxidants; D009842:Oligopeptides; D012176:Retinoids; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor; C047981:arginyl-glycyl-aspartic acid; D007372:Interferons