ABSTRACT
BACKGROUND: Liver fibrosis ranks as the second cause of death in México's productive-age population. This pathology is characterized by accumulation 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 10(11) and 1.5 x 10(11) vp/Kg, respectively) or with Ad-beta-Gal (4.5 x 10(11)) 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 regression and increase survival in experimental liver fibrosis.
Subject(s)
Genetic Therapy , Liver Cirrhosis, Experimental/therapy , Adenoviridae/genetics , Animals , Base Sequence , Carbon Tetrachloride/toxicity , DNA Primers/genetics , Gene Expression , Genetic Vectors , Humans , Immunohistochemistry , Liver/metabolism , Liver/pathology , Liver Cirrhosis, Experimental/chemically induced , Liver Cirrhosis, Experimental/genetics , Liver Cirrhosis, Experimental/pathology , Liver Regeneration/genetics , Liver Regeneration/physiology , Matrix Metalloproteinase 8/genetics , Matrix Metalloproteinase 8/metabolism , Rats , Rats, Wistar , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Urokinase-Type Plasminogen Activator/genetics , Urokinase-Type Plasminogen Activator/metabolismABSTRACT
BACKGROUND: Bile duct injuries after cholecystectomy can produce fibrous and collagen deposit tissue. Our objective was to evaluate the liver fibrosis measured in histological tissue in patients with bile duct injury after cholecystectomy. METHODS: Three normal liver biopsies and 21 from patients with bile duct injuries were studied. Group I: with three normal liver biopsies. Group II: with external abdominal fistula alone in six patients. Group III with complete bile duct obstruction in 15 patients. The surgical biliary enteric reconstructions were performed 8 weeks after bile duct injury in all cases. The fibrosis and collagen deposits were studied by Masson's trichrome and Sirius red stains and they were measured by a digital program. RESULTS: Group I showed 2 % of fibrosis tissue and 1% of collagen deposit and was considered as normal. Group II showed unexpected 1 fold more liver fibrosis and 9 fold more collagen deposit in extracellular matrix macromolecule (p < 0.05, Anova) against group I. Patients in group III, had fibrous tissue increase 43 folds more and 14 collagen folds more (p < 0.0001, Bonferroni's post hoc) versus group I. CONCLUSIONS: The patients in groups II and III showed liver fibrosis, being this more important in group III.
