Urokinase‐type plasminogen activator gene therapy in liver cirrhosis is mediated by collagens gene expression down‐regulation and up‐regulation of MMPs, HGF and VEGF

Abstract

Human urokinase-type plasminogen activator (uPA) gene administration via an adenoviral (Ad)-vector induced cirrhosis regression and ameliorated hepatic dysfunction in a model of experimental liver cirrhosis. The administration of a single dose of 6 x 10(11) viral particles per kilogram of a clinical-grade Ad-vector was evaluated after the onset of rat liver cirrhosis via degradation of deposited collagen and a substantial decrease of alpha-sma-positive cells. Also, gene expression for pro-fibrogenic molecules (Col I, III, IV, TIMP-1 and PAI-1) was clearly down-regulated. In contrast, gene expression for collagen-degrading enzymes such as MMP-13 and MMP-2 was up-regulated. These events correlated with increased amounts of proteic free-TIMP-1, i.e. non-complexed with metalloproteinases (MMPs), indicating the presence of higher amounts of active MMPs inside the liver of cirrhotic animals treated with Ad-huPA. The harmonized and concerted expression of HGF and c-met resulted in exacerbated hepatocyte proliferation, although these events did not induce an abnormal liver growth. Angiogenesis, i.e. formation of new blood vessels, was evaluated by vascular endothelial growth factor (VEGF) expression which was notably detected to be 10 times higher during the first 6 days after Ad-huPA-treatment in cirrhotic animals as compared with controls. These events provide a clearer rationale as to how Ad-huPA-induced liver regeneration on CCl(4)-induced liver fibrosis takes place.

Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies

“…MMP-8 and urokinase-type plasminogen activator stimulate collagen degradation in vivo. 78 However, the effi cacy of these drugs in humans is unknown.…”

Urokinase and its receptors in chronic kidney disease

“…In contrast uPA deficiency worsened bleomycin-induced lung fibrosis and significantly reduced fibrosis in hearts that were damaged by viral myocarditis or left ventricular pressure overload (113,117,118). Delivery of exogenous uPA as a recombinant protein or via an uPA-expressing viral vector reduced fibrosis in the lung and liver while mice with macrophages engineered to overexpress uPA spontaneously developed cardiac fibrosis (119)(120)(121)(122). In chronic renal tubulointerstitial disease the induction of endogenous uPAR reduces fibrosis severity while in a model of crescentic glomerulonephritis, genetic deficiency of either uPA or uPAR did not worsen glomerulosclerosis although the degree of glomerular inflammation was reduced in the uPAR−/− mice (22,50).…”

Adenovirus-mediated transfer of siRNA against PAI-1 mRNA ameliorates hepatic fibrosis in rats

“…Our previous study indicated that delivery of exogenous urokinase type plasminogen activator (uPA) gene into HSC-T6 decreased the amount of collagen and was accompanied by an increased expression of MMP-2, while treatment with uPA significantly ameliorated ECM deposition in experimental hepatic fibrosis [12]. In addition, a study by Bueno et al also revealed that uPA gene administration could induce cirrhosis regression and ameliorate hepatic dysfunction in experimental liver cirrhosis via upregulation of collagen-degrading enzymes such as MMP-13 and MMP-2 [13]. Plasminogen activator inhibitor-1 (PAI-1), the major physiological inhibitor of both uPA and tissue-type plasminogen activator (tPA), is a powerful fibrosis-promoting molecule and is a promising therapeutic target for fibrotic diseases.…”