Abstract
BackgroundLiver fibrosis ranks as the second cause of death in México's productive-age population. This pathology is characterized by acummulation of fibrillar proteins in hepatic parenchyma causing synthetic and metabolic disfunction. Remotion of excessive fibrous proteins might result in benefit for subjects increasing survival index. The goal of this work was to find whether the already known therapeutical effect of human urokinase Plasminogen Activator and human Matrix Metalloprotease 8 extends survival index in cirrhotic animals.MethodsWistar rats (80 g) underwent chronic intoxication with CCl4: mineral oil for 8 weeks. Cirrhotic animals were injected with a combined dose of Ad-delta-huPA plus Ad-MMP8 (3 × 1011 and 1.5 × 1011 vp/Kg, respectively) or with Ad-beta-Gal (4.5 × 1011) and were killed after 2, 4, 6, 8 and 10 days. Then, liver and serum were collected. An additional set of cirrhotic animals injected with combined gene therapy was also monitored for their probability of survival.ResultsOnly the cirrhotic animals treated with therapeutical genes (Ad-delta-huPA+Ad-MMP-8) showed improvement in liver fibrosis. These results correlated with hydroxyproline determinations. A significant decrement in alpha-SMA and TGF-beta1 gene expression was also observed. Cirrhotic rats treated with Ad-delta-huPA plus Ad-MMP8 had a higher probability of survival at 60 days with respect to Ad-beta-Gal-injected animals.ConclusionA single administration of Ad-delta-huPA plus Ad-MMP-8 is efficient to induce fibrosis regression and increase survival in experimental liver fibrosis.
Highlights
Liver fibrosis ranks as the second cause of death in México's productive-age population
Accumulation of extracellular matrix (ECM) proteins distorts the hepatic architecture by forming a fibrous scar, and the subsequent development of nodules of regenerating hepatocytes defines cirrhosis
Cirrhotic animals were injected with a dose of combined gene therapy of AdΔhuPA plus Ad-MMP8 (3 × 1011 and 1.5 × 1011 v.p/Kg, respectively) and Ad-β-Gal (4.5 × 1011) as irrelevant gene (n = 25 in each experimental group), and were sacrificed at 2, 4, 6, 8 and 10 days after treatment (Figure 1A)
Summary
Liver fibrosis ranks as the second cause of death in México's productive-age population. This pathology is characterized by acummulation of fibrillar proteins in hepatic parenchyma causing synthetic and metabolic disfunction. Remotion of excessive fibrous proteins might result in benefit for subjects increasing survival index. In México, represent the 2nd cause of dead in productive-age population [1]. This pathology is consequence of a sustained chronic hepatic injury by a variety of causes including viral, chronic alcohol abuse and cholestasis induced by prolonged biliary obstruction [2,3]. Multiple factors influencing survival of patients with hepatic cirrhosis are invoked. Cirrhosis produces hepatocellular dysfunction and increased intrahepatic resistance to blood flow, which result in hepatic insufficiency and portal hypertension [2,4]
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