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Combinatorial gene therapy renders increased survival in cirrhotic rats

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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. 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. Methods: Wistar rats (80 g) underwent chronic intoxication with CCl4: mineral oil for 8 weeks | Gálvez-Gastélum et al. Journal of Biomedical Science 2010 17 42 http www.jbiomedsci.eom content 17 1 42 a NSC Tha cost of publication In Journal of Blomodlcal Science Is boms by tlM National Science Council Taiwan JOURNAL OF BIOMEDICAL SCIENCE RESEARCH Open Access Combinatorial gene therapy renders increased survival in cirrhotic rats Francisco J Galvez-Gastelum 1 Aida A Segura-Flores1 María D Senties-Gomez1 Jose F Munoz-Valle1 and Juan S Armendariz-Borunda 1 2 Abstract Background Liver fibrosis ranks as the second cause of death in Mexico 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. Methods Wistar 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 X 1011 and 1.5 X 1011 vp Kg respectively or with Ad-beta-Gal 4.5 X 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. Results Only 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. Conclusion A single administration of Ad-delta-huPA plus Ad-MMP-8 is efficient to induce fibrosis .