Liver Cirrhosis Is Reverted by Urokinase-Type Plasminogen Activator Gene Therapy

Abstract

Liver cirrhosis represents a worldwide health problem and is a major cause of mortality. Cirrhosis is the result of extensive hepatocyte death and fibrosis induced by chronic alcohol abuse and hepatitis B and C viruses. Successful gene therapy approaches to this disease may require both reversal of fibrosis and stimulation of hepatocyte growth. Urokinase-type plasminogen activator (uPA) may serve this function, as it is an initiator of the matrix proteolysis cascade and induces hepatocyte growth factor expression. In a rat cirrhosis model, a single iv administration of a replication-deficient adenoviral vector encoding a nonsecreted form of human uPA resulted in high production of functional uPA protein in the liver. This led to induction of collagenase expression and reversal of fibrosis with concomitant hepatocyte and improved liver function. Thus, uPA gene therapy may be an effective strategy for treating cirrhosis in humans.

Modulation of extracellular matrix by nutritional hepatotrophic factors in thioacetamide-induced liver cirrhosis in the rat

“…Other substances have proven to be effective: vitamins C, E and C + E (24), losartan (28), gliotoxin (24), pirfenidone (29), relaxin (30), and Han-Dan-Gan-Lee (31) also reduced fibrosis in rat livers. Hepatic growth factor (22), halofuginone (32) and adenovirus with urokinase plasminogen activator (25) induced collagen reduction in cirrhosis models. It should be pointed out that treatment with pirfenidone reduced 40% of the fibrosis induced by CCl 4 (23).…”

“…The reduction of ALT (-17.6%) and AST (-12.2%) also points to a reduced hepatocellular necrosis, decreasing the cycles of cell death and fibrotic regeneration that are characteristic of the cirrhotic process. Other treatments also improved hepatic conditions in fibrosis and cirrhosis models with down-regulation of enzymes of hepatic function, such as gliotoxin (21), hepatic growth factor (22), pirfenidone (23), vitamins C and E (24), urokinase plasminogen activator (25), and partial hepatectomy (26).…”

“…In fibrosis models, interleukin-10 down-regulated TIMP-1 and MMP-2 (34); relaxin down-regulated collagen-α1 and TIMP-1 (30) and pirfenidone reduced TGF-β1, TIMP-1, and procollagen α1(I) production (29). In cirrhotic models, adenovirus with urokinase plasminogen activator, increased gene expression of collagenases (25), and halofuginone reduced gene expression of collagen-α1 (35). Progranulin protein and mRNA were found in hepatic and intestinal cells of cirrhotic rats.…”

Adenovirus-mediated gene transfer of interferon α improves dimethylnitrosamine-induced liver cirrhosis in rat model

“…31,32 However, none of those strategies has been examined for an antiviral effect on HCV. We found that the AxCA-rIFN vector inhibited HCV replication in vitro (unpublished data), and the anti-HCV effect may add an advantage to the IFN-a gene therapy for HCV-induced LC.…”

Inhibition of Collagen α1(I) Expression by the 5′ Stem-Loop as a Molecular Decoy

“…They are based on enhancing the degradation of extracellular matrix by overexpressing urokinase-type plasminogen activator (34) or matrix metalloproteinase 1 (35) or on stimulation of hepatocyte proliferation by expression of hepatocyte growth factor (36). The molecular decoys described here act by a novel mechanism of preventing excessive production of fibrillar collagens.…”