Melatonin protects the liver and erythrocytes against oxidative stress in cirrhotic rats / Melatonina protege o fígado e eritrócitos do estresse oxidativo em ratos cirróticos

CONTEXT: Cirrhosis is a progressive chronic hepatopathy which constitutes an irreversible stage of liver dysfunction. OBJECTIVES: To evaluate the oxidative stress in the blood of cirrhotic rats treated with the antioxidant melatonin. METHODS: Cirrhosis was induced through inhalation of carbon tetrachloride. Liver integrity was evaluated by measuring serum enzymes, oxidative damage measured by lipoperoxidation, and antioxidant enzyme activity in erythrocytes. Lipoperoxidation, total nitrates, collagen, and histology by picrosirius staining were evaluated in the livers of these animals (n = 15), which were divided in three groups: control, carbon tetrachloride, and carbon tetrachloride + melatonin. Melatonin (20 mg/kg) was administered intraperitoneal from week 10 of carbon tetrachloride inhalation. In order to shorten the cirrhosis induction time, phenobarbital (0.3 g/L) was added to the animals' drinking water. RESULTS: A significant impairment in the liver integrity of melatonin-treated animals as compared to cirrhotic animals was observed. In rat erythrocytes and liver, lipoperoxidation was significantly increased in the cirrhotic rats as compared to controls, as measured through thiobarbituric acid reactive substances, and significantly decreased in melatonin-treated animals as compared to cirrhotic ones. In blood, a decrease in superoxide dismutase and glutathione peroxidase enzymes was detected in the cirrhotic group as compared to the control group, with increased superoxide dismutase activity when melatonin was administered. A reduction in the levels of total nitrates was detected in the hepatic tissue of the animals in the carbon tetrachloride group as compared to the control group and an increase of these levels in the carbon tetrachloride + melatonin group. As for hepatic collagen, we found a significant increase in the carbon tetrachloride group as compared to the controls and a regression of these values in the treated group. ...

CONTEXTO: A cirrose é uma hepatopatia crônica e progressiva que constitui estágio irreversível de disfunção hepática. É associada a alterações na circulação sistêmica. OBJETIVOS: Avaliar o estresse oxidativo no sangue de ratos cirróticos e tratados com antioxidante melatonina. MÉTODOS: A cirrose foi induzida através da inalação de tetracloreto de carbono. Foram avaliadas as provas de integridade hepática através das medidas das enzimas séricas, o dano oxidativo medido pela lipoperoxidação e a atividade das enzimas antioxidantes no eritrócito. No fígado desses animais, foram avaliados a lipoperoxidação, os nitratos totais, colágeno e histologia através de picrosíruis. Os animais (n = 15) foram divididos em três grupos experimentais: controle, tetracloreto de carbono e tetracloreto de carbono + melatonina. A melatonina foi administrada por via intraperitonial após a 10ª semana de inalação na concentração de 20 mg/kg. Com o objetivo de abreviar o tempo de indução, foi administrado para todos animais, fenobarbital na água de beber na concentração de 0,3 g/L. RESULTADOS: Observou-se redução significativa nas provas de integridade hepática nos animais tratados com melatonina, em relação aos animais cirróticos. Nos eritrócitos e fígados dos ratos, foi observado aumento significativo da lipoperoxidação nos ratos cirróticos em comparação com os controles, através da medida das substâncias que reagem ao ácido tiobarbitúrico, e redução nos animais tratados com melatonina. No sangue, observou-se diminuição dos valores das enzimas superóxido dismutase e glutationa peroxidase do grupo cirrótico em comparação ao grupo controle, elevando a atividade da superóxido dismutase quando administrada melatonina. Na avaliação dos nitratos totais, no tecido hepático, observou-se redução dos valores nos animais do grupo tetracloreto de carbono em comparação ao grupo CO e um aumento desses valores nos ratos do grupo tratado com melatonina. Na medida do colágeno ...

Hepatoprotective effect of water soluble extract of Coleus barbatus on cholestasis on young rats / Efeito hepatoprotetor do extrato aquoso de Coleus barbatus na colestase em ratos jovens

PURPOSE: To test the effects of water extract of Coleus barbatus (WEB) on liver damage in biliary obstruction in young rats. METHODS: Forty 21 day-old male Wistar rats were divided into four groups of ten 21 day old (P21) submitted to sham or actual operation (S or L) combined with WEB or Water (B or A). At P48 pentobarbital sleeping time (ST) was measured. At P49 they were submitted to euthanasia to determine of serum activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), liver wet weight (PFF) and, on hepatic histological slides, the frequency of mitoses (FM), the number of necrotic areas (NN), intensity of fibrosis (IF) and intensity of ductal proliferation (IPD). Two Way ANOVA, the S.N.K. test and the Wilcoxon test for paired multiple comparisons were employed to study the effects of cholestasis and those of EAB and their interactions. The Pearson's coefficient of linear correlation of between paired histological variables separately for the groups LA and LD was determined. The test results were considered statistically significant when the p of alpha error <0.05. RESULTS: Cholestasis increased the TS, ALT, AST, PFF, MI, NN, IF and IPD. The EAB decreased the TS and IM in the animals without cholestasis (sham operated animals). The EAB decreased the TS, ALT, AST, PFF, MI, NN and IF of the cholestatic animals. In the LA group there was a positive correlation between the IPD and the IF, a negative correlation between the IPD and the FM and a negative correlation between the IF and the FM. In the LD group there was a negative correlation between the NN and the IPD. CONCLUSIONS: In the absence of cholestasis the EAB reduces the pentobarbital sleeping time and decreases the frequency of mitoses. The EAB has a hepatoprotective effect on the biliary cirrhosis secondary to extra-hepatic biliary obstruction.

OBJETIVO: Testar os efeitos do extrato aquoso de Coleus barbatus (EAB) na cirrose biliar secundária por obstrução das vias biliares extra-hepáticas em ratos jovens. MÉTODOS: Quarenta ratos Wistar machos com 21 dias de vida (P21), foram distribuídos em quatro grupos de 10 animais, submetidos a operação simulada ou dupla ligadura e ressecção do ducto biliar (S ou L) combinados EAB e a Água (B ou A). No P48, foi medido o tempo de sono com o pentobarbital (TS). No P49, foram submetidos a eutanásia para a determinação das atividades séricas do aspartato aminotransferase (AST) e da alanina aminotransferases (ALT); após a eutanásia foram avaliados o peso fresco do fígado (PFF) e, em cortes histológicos do fígado, a freqüência de mitoses (FM), o número de áreas de necrose (NN), a intensidade da fibrose (IF) e da proliferação ductal (IPD). Os efeitos da colestase, os do EAB e suas interações foram testados pela ANOVA com dois fatores, e as comparações múltiplas pareadas foram realizadas pelo teste de S.N.K ou teste de Wilcoxon. Também foi determinada a correlação linear de Pearson entre as variáveis histológicas duas a duas separadamente para os grupos LA e LD. O nível de significância estatística para os vários testes foi de p do erro alfa <0,05. RESULTADOS: A colestase aumentou significativamente o TS, a ALT, a AST, o PFF, a MI, o NN, a IF e a IPD. O EAB diminuiu o TS e a IM nos animais sem colestase (operação simulada). O EAB diminuiu o TS, a ALT, a AST, o PFF, a MI, o NN e IF na colestase. No grupo LA houve correlação positiva entre a IPD e a IF, correlação negativa entre a IPD e a FM e correlação negativa entre a IF a FM. No grupo LD houve correlação negativa entre o NN e a IPD. CONCLUSÕES: Na ausência de colestase o EAB encurta o tempo de sono e diminui a freqüência de mitoses. O EAB apresenta efeito hepatoprotetor no modelo de cirrose biliar secundária a obstrução biliar extra-hepática.

Role of N-acetylcysteine on fibrosis and oxidative stress in cirrhotic rats / Papel da N-acetilcisteína na fibrose e estresse oxidativo em ratos cirróticos

BACKGROUND: Hepatic cirrhosis is the final stage of liver dysfunction, characterized by diffuse fibrosis which is the main response to the liver injury. The inhalatory carbon tetrachloride is an effective experimental model that triggers cirrhosis and allows to obtain histological and physiological modifications similar to the one seen in humans. AIM: To investigate the effects of N-acetylcysteine (NAC) on the fibrosis and oxidative stress in the liver of cirrhotic rats, analyzing liver function tests, lipoperoxidation, activity of glutathione peroxidase enzyme, collagen quantification, histopathology, as well as the nitric oxide role. METHODS: The animals were randomly in three experimentals groups: control (CO); cirrhotic (CCl4) and CCl4 + NAC. Evaluate the lipid peroxidation, the glutathione peroxidase enzyme, the collagen and the expression of inducible nitric oxide synthase (iNOS). RESULTS: The cirrhotic group treated with N-acetylcysteine showed trough the histological analysis and collagen quantification lower degrees of fibrosis. This group has also shown less damage to the cellular membranes, less decrease on the glutathione peroxidase levels and less expression of inducible nitric oxide synthase when matched with the cirrhotic group without treatment. CONCLUSION: N-acetylcysteine seams to offer protection against hepatic fibrosis and oxidative stress in cirrhotic rat livers.

RACIONAL: A cirrose é o estágio final da disfunção hepática, sendo caracterizada por fibrose difusa, que compõe a resposta principal do organismo ao dano hepático. O tetracloreto de carbono inalatório é um modelo experimental efetivo, que desencadeia a cirrose e permite obter modificações histológicas e fisiológicas similares às vistas em humanos. OBJETIVO: Investigar os efeitos da N-acetilcisteina (NAC) sobre a fibrose e o estresse oxidativo no fígado de ratos cirróticos, analisando as provas hepáticas, a lipoperoxidação, a atividade da enzima glutationa peroxidase, a quantificação do colágeno, a histopatologia, bem como o papel do óxido nítrico. MÉTODOS: Os animais foram divididos em três grupos experimentais: controle (CO); cirrótico (CCl4) e CCl4 + NAC. Foram avaliados a lipoperoxidação, a enzima glutationa peroxidase, a histologia hepática, a quantificação de colágeno e a expressão da óxido nítrico síntase induzível (iNOS). RESULTADOS: O grupo cirrótico tratado com a NAC demonstrou, através da análise histológica e da quantificação de colágeno, menores graus de fibrose. Este grupo demonstrou, ainda, menos dano às membranas celulares, menor decréscimo nos níveis de glutationa peroxidase e menor expressão da iNOS quando comparado com o grupo cirrótico sem tratamento. CONCLUSÃO: A NAC parece oferecer proteção contra a fibrose hepática e o estresse oxidativo no fígado de ratos cirróticos.

Inhibitory Effect of Angiotensin Blockade on Hepatic Fibrosis in Common Bile Duct-ligated Rats / 대한간학회지

BACKGROUNDS AND AIMS: Angiotensin receptors are found on hepatic stellate cells, which participate in hepatic fibrosis. Therefore, it is presumed that angiotensin has a role in hepatic fibrosis. The aim of this study was to evaluate the effects of angiotensin blockade on inhibition of hepatic fibrosis in cirrhotic rat model. Material and METHODS: Cirrhosis with portal hypertension was produced by common bile duct ligation (BDL) in the adult Sprague-Dawley rats. They were classified into 4 groups (each group n=6) as follows; G1: BDL without drug, G2: BDL+captopril 100 mg/kg/day beginning 2 weeks after BDL, G3: BDL+captopril 100 mg/kg/day, starting just after BDL, G4: BDL+losartan 10 mg/kg/day, starting just after BDL. After 4 weeks following BDL, hepatic fibrosis was histomorphologically analyzed by Batts & Ludwig score. Alpha smooth muscle actin by immunohistochemical stain, hydroxyproline contents of liver tissue by spectrophotometry and expression of collagen, procollagen, and TGF-beta by real-time PCR were measured. RESULTS: Batts & Ludwig score were 3.8, 3.0, 2.6,and 2.6 in G1, G2, G3, and G4, respectively. The expression of alpha-SMA was significantly lower in G3 and G4 than in G1; 11.9%, 10.9%, 2.6%, and 1.1% in G1, G2, G3, and G4, respectively (p<0.05). The concentration of hydroxyproline (microgram/g liver tissue) was lower in G3 and G4 compared with G1 (p<0.05). Also, the administration of angiotensin blockade just after BDL significantly reduced the expression of collagen, procollagen, and TGF-beta mRNA. CONCLUSIONS: Angiotensin blockades are effective in the prevention of hepatic fibrosis in BDL rats.

Capillaria hepatica in rats: focal parasitic hepatic lesions and septal fibrosis run independent courses

Capillaria hepatica causes two main lesions in the liver of rats: multifocal chronic inflammation, directly related to the presence of disintegrating parasites and their eggs, and a process of systematized septal fibrosis. The comparative behavior of these two lesions was investigated in rats experimentally infected with 600 embryonated eggs, following either corticosteroid treatment or specific antigenic stimulation, in an attempt to understand the relationship between these two lesions, and the pathogenesis of septal fibrosis. The two treatments differently modified the morphological aspects of the focal parasitic-related lesions, but did not interfere with the presentation of diffuse septal fibrosis, although a mild decrease in the degree of fibrosis occurred in corticoid-treated animals. These findings indicate that although the two lesions are C. hepatica induced, they are under different pathogenetic control, the induction of septal fibrosis being triggered during early infection to follow an independent pathway.

Effect of interferon-alpha on experimental septal fibrosis of the liver - study with a new model

Interferon-alpha is used in antiviral therapy in humans, mainly for viral hepatitis B and C. An anti-fibrotic effect of interferon has been postulated even in the absence of anti-viral response, which suggests that interferon directly inhibits fibrogenesis. Rats infected with the helminth Capillaria hepatica regularly develop diffuse septal fibrosis of the liver, which terminates in cirrhosis 40 days after inoculation. The aim of this study was to test the anti-fibrotic effect of interferon in this experimental model. Evaluation of fibrosis was made by three separate methods: semi-quantitative histology, computerized morphometry and hydroxyproline measurements. Treatment with interferon-alpha proved to inhibit the development of fibrosis in this model, especially when doses of 500,000 and 800,000 IU were used for 60 days. Besides confirming the anti-fibrotic potential of interferon-alpha on a non-viral new experimental model of hepatic fibrosis, a clear-cut dose-dependent effect was observed

Efeito da colchicina sobre a cirrose hepática, em ratos, induzida por tetracloreto de carbono / Effect of colchicine on hepatic cirrhosis, in rats, induced by carbon tetrachloride

Os autores avaliam o efeito da colchicina sobre a cirrose, em ratos, induzida por tetracloreto de carbono (CCI4). Ratas Wistar foram divididas em grupos controles e em grupos tratados com colchicina, 10ug/100g/dia, e CCI4, 5ug/100g/dia, de colchicina e CCI4 ou apenas CCI4. Foi verificado que os animais que receberam CCI4 isolado ou associado à colchicina mostraram aumento da atividade da TGO, TGP e FA e reduçäo nos níveis séricos de albumina. O exame anatomopatológico do fígado dos animais desses grupos mostrou a presença de infiltrado inflamatório, esteatose, necrose, fibrose, proliferaçäo dos ductos biliares e regeneraçäo nodular. Além disso, nos rins desses animais foi detectada nefrite intersticial leve. Näo houve alteraçöes, entre os diferentes grupos, em relaçäo aos eletrólitos, uréia e creatinina

Fibrosis hepatica y progesterona

Con el fin de estudiar la acción de la Prog sobre la fibrosis hepática, fue inducida esta alteración por medio de la ingesta de C14C y etanol, en 55 conejos, entre 1 y 2 años, raza New Zealand; desarrolando la fibrosis en 6 meses. El grupo de animales tratados con Prog, ya sea desde el comienzo o después de 180 días de recibir el tóxico, presentaba disminución o menos fibrosis; así como protección del hepatocito, que se evidenciaba por la nobalonización o vacuolización de las células, no infiltrado inflamatorio, ni tampoco metamorfosis grasa. Si algunas de estas alterraciones habían aparecido, al iniciar el tratamiento con Prog disminuían gradualmente hasta desaparecer. Los datos de laboratorio tuvieron una diferencia altamente significativa a los 60 y 180 días entre los grupos que recibían el tóxico y los que revibían Prog, ya sea desde el comienzo o diferida. La Prog, como se ha visto en cultivos de fibroblastos fetales y en el tratamiento de tumores desmoides o adhesiones quirúrgicas, destruye los fibroblastos y por consiguiente disminuye el tamaño de estos tumores y la cohesión de las adherencias. La razón de no haberse hallado una resolución total de la cirrosis (aunque si una disminución manifiesta de la fibrosis) puede deberse a la actividad de miofibroblastos que provocan la retracción del tejido hepático dañado