Hepatic cirrhosis by thioacetamide in rats: study of the experimental model by intraperitoneal administration

Abstract

Hepatic cirrhosis is a chronic lesion resulting from a prolonged injury. It is morphologically characterized by the formation of parenchymal regenerative nodules, which are surrounded by fibrous septa. Cirrhosis usually occurs associated to serious alterations of the hepatic function and architecture. The animal models of hepatic cirrhosis are important for the study of the mechanisms of the illness and its related treatment. In rodent models of induction by thioacetamide, the regenerative nodules are prominent and the histological pattern is similar to that found in the micronodular human cirrhosis. It is a very useful model to study antifibrotic drugs. The thioacetamide can be given by oral or intraperitoneal route. Studies of the model based on oral administration have reported adaptation of rats to the drug, weight gain, serum markers of hepatic lesion close to normal levels and large individual variation. The intraperitoneal via showed much less variation, however, the phenomenon of adaptation to thioacetamide has not yet been studied in this model, which we intend to do in this project giving progressively higher doses to the rats. We will also study the cells and molecules involved with extracellular matrix behavior. Three groups of Wistar rats will receive an initial dose of 20 mg/100g of body weight of thioacetamide. Group A will receive the same dose for 14 weeks. Group B will receive 20% more thioacetamide in the second half of the experiment. Group C doses will be increased by 10% each 24 days until the end of the 14 weeks period. After euthanasia, samples of liver and blood will be taken and directed to histopathological examination, immunohistochemistry, collagen quantification, blood serum analysis for markers of hepatic lesion and real-time PCR analysis. The objectives of this work are: a) to obtain a cirrhotic status by intraperitoneal route that shows alterations of liver architecture, with loss or maintenance of body weight and increased levels of serum markers of hepatic lesion avoiding adaptation to thioacetamide by progressive doses; b) to get information on the comparative behavior of the stellate cells (HSC) and the expression of mRNA of molecules involved in the cirrhotic processes, as TGFb1, Type I collagen, MMPII (metalloproteinase II) and TIMP I (tissue inhibitor of metalloproteinase I). (AU)