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Master's Dissertation
DOI
https://doi.org/10.11606/D.10.2008.tde-09012009-091225
Document
Author
Full name
Tânia Cristina Lima
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2008
Supervisor
Committee
Blazquez, Francisco Javier Hernandez (President)
Pinto, Frederico Azevedo da Costa
Silva, José Roberto Machado Cunha da
Title in Portuguese
Cirrose hepática induzida por tioacetamida: estudo do modelo por injeção intraperitonial a longo prazo em ratas Wistar
Keywords in Portuguese
Cirrose
Fígado
Função Hepática
Rato
Tioacetamida
Abstract in Portuguese
A baixa sensibilidade dos animais à droga e a função hepática pouco alterada são as principais dificuldades para o desenvolvimento da cirrose hepática experimental. A proposta deste trabalho foi aprimorar o modelo de cirrose por injeção intraperitoneal de tioacetamida (TAA) a fim de reduzir a adaptação dos animais ao fármaco. Foram utilizados 5 grupos de fêmeas de ratos Wistar: A (200 mg TAA/kg); B (aumento de 20% aos 48 dias); C (aumento de 10% a cada 24 dias); D (aumento de 15% a cada 24 dias); E (solução salina). Os animais foram injetados 3 vezes por semana durante 14 semanas. Foram realizadas coletas sanguíneas, por punção cardíaca, no início, no final do experimento e antes dos aumentos de dose, para análise dos marcadores de função hepática. A avaliação comportamental foi efetuada pelo método do labirinto em cruz elevado (LCE). Amostras de fígado foram colhidas e submetidas ao processamento para microscopia de luz. Os animais tratados com TAA apresentaram piloereção, icterícia e cromodacriorréia. Os testes do LCE demonstraram estresse e/ou ansiedade nesses animais. Os fígados cirróticos apresentaram nódulos regenerativos e lesões hemorrágicas na superfície. O ganho de peso foi semelhante entre os grupos tratados, porém, inferior ao do grupo E. Os danos de função hepática foram mais acentuados nos grupos em que houve aumento de dose, entretanto, a mortalidade do grupo D foi elevada (44%). O tratamento com TAA levou ao desenvolvimento de cirrose com formação de nódulos regenerativos circundados por septos fibrosos e desarranjo da arquitetura hepática. A deposição de colágeno foi maior nos grupos B e C. O grupo D apresentou quantidade de colágeno semelhante a do grupo A. O exame histopatológico demonstrou intensa proliferação de células ovais e hiperplasia de ductos biliares com produção de muco ácido. Foi observada presença de hemossiderina, hepatócitos balonizados, lesões nucleares e células inflamatórias. A administração de TAA provocou ainda o desenvolvimento de lesões pré-neoplásicas, sugerindo possível efeito carcinogênico dessa substância. Os resultados demonstraram que os grupos B e C foram os mais eficazes no desenvolvimento da cirrose experimental. O grupo D, apesar do aumento maior na dose, apresentou resultados similares aos do grupo A (dose constante) e alta mortalidade, selecionando animais resistentes à droga. Assim, recomenda-se o modelo de indução do grupo B por apresentar menor mortalidade (5%), menor influência no aspecto emocional e quadro cirrótico tão grave quanto o dos animais do grupo C.
Title in English
Hepatic cirrhosis induced by thioacetamide: study of the model of intraperitoneal long term administration in Wistar rats
Keywords in English
Cirrhosis
Hepatic function
Liver
Rat
Thioacetamide
Abstract in English
The low sensitivity of animals to drugs and the lack of changes in liver function are the main difficulties for the development of experimental liver cirrhosis. The aim of this study was improving the model of cirrhosis by intraperitoneal injection of thioacetamide (TAA) to reduce the animal adaptation to the drug. We used 5 groups of female Wistar rats: A (200 mg TAA/kg), B (increase of 20% to 48 days), C (increase of 10% every 24 days), D (increase of 15% every 24 days), E (saline). The animals were injected 3 times a week for 14 weeks. Blood samples were collected by cardiac puncture at the start and at the end of the experiment as well as before each dose increment, for analysis of markers of liver function. The behavioral assessment was done by the method of elevated plus-maze. Samples of liver were collected and processed to light microscopy. The animals treated with TAA showed piloerection, jaundice and chromodacryorrhea. Behavioral test showed stress and/or anxiety in these animals. The liver cirrhosis showed regenerative nodules and hemorrhagic lesions on the surface. Weight gain was similar among the groups treated, however, all of them were smaller than those of group E. The damage of the liver function was more pronounced in groups where the dose was increased over the experimental period, however, the mortality of group D was higher (44%). Treatment with TAA led to the development of cirrhosis with formation of regenerative nodules surrounded by fibrous septa and hepatic architecture disruption. The deposition of collagen was higher in groups B and C, whereas group D was similar to group A. Histopathologic evaluation showed intense proliferation of oval cells and bile duct hyperplasia, with production of acid mucin. It was observed the presence of hemosiderin, hepatocyte ballonization, nuclear lesions and inflammatory cells. The administration of TAA led to the development of neoplastic lesions, suggesting possible carcinogenic effect of this substance. The results showed that the treatment of groups B and C were most effective in the development of experimental cirrhosis. Despite that animals of group D received an increment in their TAA dose, their results seems similar to those of group A but with high mortality, probably because the treatment selected resistant animals to the drug. Therefore, it is recommended the model of induction of group B due to the lower mortality (5%), less influence on the emotional aspect and development of cirrhosis as severe as that the rats of group C.
 
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Publishing Date
2009-02-04
 
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