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At least 199 records · Page 11Linked to original sources
PubMed1999

Evaluation of different models of experimentally induced liver cirrhosis for MRI research with correlation to histopathologic findings.

RATIONALE AND OBJECTIVES: Three models of experimentally induced liver cirrhosis were evaluated for MRI research on chronic liver disease. The influence of different histopathologic changes in liver fibrosis and cirrhosis on relaxation times and signal intensities was studied in vitro and in vivo. METHODS: Liver fibrosis and cirrhosis in rats was induced by oral or subcutaneous administration of carbon tetrachloride (CCl4) or by thioacetamide (TAA) in drinking water. On histology, the degree of liver fibrosis and cirrhosis, fatty infiltration, iron accumulation, and inflammatory changes were measured semiquantitatively. The amount of connective tissue was quantitatively determined by morphometry. The results were correlated with T1 and T2 relaxation times and signal intensities of the liver studied in vitro by relaxometry and in vivo by MRI. RESULTS: In both groups with CCl4 administration, histology revealed different degrees of liver fibrosis and cirrhosis. Subcutaneous injection of CCl4 also resulted in increased fatty infiltration. On the contrary, TAA produced complete liver cirrhosis in all animals. Overall, there was a good correlation between the liver T2 relaxation time and the amount of connective tissue in liver fibrosis and cirrhosis. However, the degree of liver fibrosis and cirrhosis was also strongly correlated with the degree of inflammatory changes. In the group with CCl4 administration, there was a good correlation between the fatty infiltration and the T1 relaxation time, as well as with the liver signal intensity on the T1-weighted gradient echo sequence. An increased iron accumulation was also correlated with the degree of liver fibrosis/cirrhosis; however, there was no significant influence of the iron on relaxation times or signal intensities. CONCLUSIONS: The TAA model is easier to perform and more reliable in liver cirrhosis induction than the CCl4 models. Although there is a positive correlation between the T2 relaxation times and the degree of liver fibrosis/cirrhosis, this probably results from the associated inflammatory changes and is not caused by the increased amount of connective tissue.

Animals↗
PubMed1991

Liver tumors in cirrhosis: experimental study with SPIO-enhanced MR imaging.

The influence of cirrhosis on superparamagnetic iron oxide (SPIO)-enhanced magnetic resonance (MR) imaging of the liver was studied in 31 rats. Experimental models included carbon tetrachloride-induced cirrhosis and liver engrafting of rhabdomyosarcoma S4T cells. Hepatic uptake of SPIO measured with relaxometry decreased dramatically with histologic grade, while splenic uptake increased; the same results were achieved by calculating K values. Imaging of 13 tumorous cirrhotic rats confirmed these results by showing a muted decrease in liver signal intensity on spin-echo images after injection of SPIO. Nevertheless, all intrahepatic tumors could be visualized, as confirmed by postmortem examination. On gradient-echo images, postinjection contrast between the tumor and the liver was not affected by cirrhosis. Thus, despite strong impairment of hepatic uptake in cirrhosis, the diagnostic efficacy of MR imaging with SPIO did not seem to be significantly affected.

Animals↗
PubMed1999

The Ras antagonist, farnesylthiosalicylic acid (FTS), inhibits experimentally-induced liver cirrhosis in rats.

BACKGROUND/AIMS: Protooncogenes may play an important role, not only in carcinogenesis, but also in the regulation of normal cellular proliferation and differentiation. Several studies have indicated increased expression of the Ras protooncogenes in the liver in animal models and in patients with liver cirrhosis. The aim of the present study was to examine whether a synthetic Ras antagonist, S-farnesylthiosalicylic acid (FTS), which specifically dislodges Ras from the membrane of Ras-transformed fibroblasts (EJ cells), can prevent experimentally-induced liver cirrhosis in rats. METHODS: Cirrhosis was induced in male Wistar rats by intraperitoneal administration of thioacetamide (200 mg/kg twice weekly for 12 weeks). The Ras antagonist, farnesylthiosalicylic acid (FTS, 5 mg/kg), was administered during the study period 3 times a week. Ras expression in the liver was determined by Western blot analysis with pan anti-Ras antibodies and by immunohistochemistry. RESULTS: Rats treated with thioacetamide and the Ras antagonist, farnesylthiosalicylic acid (FTS), for 12 weeks had lower histopathologic scores of fibrosis and inflammation (p-values of 0.003 and 0.008, respectively) than those treated with thioacetamide only. There were no differences between the histopathologic scores in vehicle (control) and in Ras-antagonist (FTS) only treatments. Analysis of hepatic hydroxyproline levels from the two thioacetamide-treated groups and controls confirmed the histopathologic scores (7.7+/-0.9 mg/g protein in the TAA-treated vs. 3.8+/-0.5 mg/g protein in the TAA+FTS treated group, p = 0.007). Ras levels, determined by Western blot analysis, were markedly increased in the livers treated with TAA (17-fold over control) and significantly decreased (by about 70%) in the livers of rats treated with TAA and FTS. Studies in isolated human hepatic stellate cells demonstrated that FTS inhibited both DNA synthesis and migration of those cells (p<0.05). CONCLUSION: These results indicate that inhibition of Ras expression in the liver during fibrogenesis, prevents the development of experimentally-induced hepatic cirrhosis.

Animals↗
PubMed1986

Effects of the platelet-activating factor antagonist BN 52021 on the hemodynamics of rats with experimental cirrhosis of the liver.

Previous studies from this laboratory have shown that rats with experimental cirrhosis of the liver induced by the combined administration of oral phenobarbital and inhaled carbon tetrachloride show an hyperdynamic status with enhanced cardiac output (CO), and decreased mean arterial pressure (MAP) and peripheral vascular resistance (PVR). Cirrhotic rats also showed an increased vascular permeability. All these phenomena are similar to some of the known effects of the systemic infusion of low doses of synthetic platelet-activating factor into the systemic circulation of normal rats. The measurement of the levels of platelet-activating factor in samples of blood demonstrated significantly higher levels in cirrhotic (2.65 +/- 0.39; n = 10) than in control rats (1.50 +/- 0.57 ng/ml; n = 10; p less than 0.05). The hemodynamic changes induced by the intravenous injection of the platelet-activating factor receptor antagonist BN 52021 (5 mg/kg body weight) have been measured in 10 control and 10 cirrhotic male Wistar rats, using a radioactive microsphere technique. BN 52021 induced no significant hemodynamic changes in control animals. However, in cirrhotic animals it induced a significant decrease in CO with increase in PVR. MAP increased slightly but not significantly. From these data it can be deduced that platelet-activating factor plays a role in the hemodynamic derangement shown by cirrhotic rats and that these derangement can be reversed by BN 52021, a highly selective antagonist of the platelet-activating factor receptor.

Animals↗
PubMed2006

Urokinase-type plasminogen activator gene therapy in liver cirrhosis is mediated by collagens gene expression down-regulation and up-regulation of MMPs, HGF and VEGF.

Human urokinase-type plasminogen activator (uPA) gene administration via an adenoviral (Ad)-vector induced cirrhosis regression and ameliorated hepatic dysfunction in a model of experimental liver cirrhosis. The administration of a single dose of 6 x 10(11) viral particles per kilogram of a clinical-grade Ad-vector was evaluated after the onset of rat liver cirrhosis via degradation of deposited collagen and a substantial decrease of alpha-sma-positive cells. Also, gene expression for pro-fibrogenic molecules (Col I, III, IV, TIMP-1 and PAI-1) was clearly down-regulated. In contrast, gene expression for collagen-degrading enzymes such as MMP-13 and MMP-2 was up-regulated. These events correlated with increased amounts of proteic free-TIMP-1, i.e. non-complexed with metalloproteinases (MMPs), indicating the presence of higher amounts of active MMPs inside the liver of cirrhotic animals treated with Ad-huPA. The harmonized and concerted expression of HGF and c-met resulted in exacerbated hepatocyte proliferation, although these events did not induce an abnormal liver growth. Angiogenesis, i.e. formation of new blood vessels, was evaluated by vascular endothelial growth factor (VEGF) expression which was notably detected to be 10 times higher during the first 6 days after Ad-huPA-treatment in cirrhotic animals as compared with controls. These events provide a clearer rationale as to how Ad-huPA-induced liver regeneration on CCl(4)-induced liver fibrosis takes place.

Adenoviridae↗
PubMed1980

The susceptibility of hepatic collagen to homologous collagenase in human and experimental cirrhosis of the liver.

The susceptibility of hepatic collagen to homologous collagenase in human and experimental CCl4 cirrhosis of the liver has been explored in vitro by exposure of cryostat liver sections to the corresponding enzymes for different time periods. The morphology and extent of collagen degradation was studied by the Picrosirius red/polarizing microscopy technique. The results of various experiments indicate that collagen present in cryostat sections of both human and rat normal and cirrhotic livers is resistant to trypsin digestion for periods of exposure of up to 48 hours but that heating the sections to 60 C for 1 hour renders the collagen susceptible to degradation by trypsin. Incubation of cryostat liver sections with bacterial collagenase revealed progressive degradation of collagen with a uniform pattern of changes in the original color and diameter of the fibers. Exposure of liver sections to homologous collagenases gave rise to the same pattern of changes observed with bacterial collagenase, although less extensive when equal incubation periods were compared. Nevertheless, sufficiently prolonged incubation of liver sections with their homologous collagenases eventually showed degradation of all collagen present in all normal and cirrhotic liver sections. These observations suggest that in the presence of non rate-limiting concentrations of homologous collagenase, the susceptibility of hepatic collagen to the corresponding degrading enzyme is probably not responsible for the irreversibility of the disease.

Animals↗
PubMed1989

Effect of dietary sodium intake on the pressor reactivity to angiotensin II in rats with experimental cirrhosis of the liver.

The present experiments were designed to evaluate vascular reactivity to angiotensin II in rats with experimental cirrhosis of the liver (induced with CCl4 and phenobarbital) before ascites appearance. The systemic pressor response to angiotensin II in conscious animals and the contractile effect of angiotensin II in isolated femoral arteries were studied. In addition, the effect of high sodium intake on these parameters was also analyzed. Both renin and aldosterone plasma concentrations were similar in control and cirrhotic rats on the normal or on the high sodium diet. Basal mean arterial pressure was higher in control rats than in cirrhotic rats on the normal sodium (116 +/- 4 vs. 101 +/- 4 mmHg (1 mmHg = 133.3 Pa), p less than 0.05) or on the high sodium diet (118 +/- 7 vs. 98 +/- 6 mmHg). No differences in plasma renin activity or plasma aldosterone were found between control and cirrhotic rats. Upon injection of angiotensin II, control rats show a dose-dependent increase in mean arterial pressure which is higher in high sodium than in normal sodium rats. Cirrhotic rats showed a lower hypertensive response to angiotensin II than their corresponding control rats. In addition, no difference between pressor responses to angiotensin II was observed when normal sodium and high sodium cirrhotic rats were compared. On application of angiotensin II, femoral arteries of control and cirrhotic rats exhibited a dose-dependent contraction. However, maximal contraction was higher in high sodium control rats (145 +/- 12 mg) than in normal sodium control rats (99 +/- 6 mg, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMedDate not supplied

Protective effect of IGF-1 on experimental liver cirrhosis-induced common bile duct ligation.

BACKGROUND/AIMS: The causes of malnutrition in liver cirrhosis are multifactorial. Levels of IGF-1 (insulin like growth factor-1) that is a crucial regulator of intermediary metabolism decreases. The aim of this study was to analyze the effect of IGF-1 supplementation during liver cirrhosis induced by common bile duct ligation. METHODOLOGY: Rats were divided into five different groups: One sham and four experimental groups. Rats in three of four groups were treated with 2 micrograms/day IGF-1 with a different time of experiment in each group. Blood biochemical parameters, tissue malondialdehyde, glutathione levels and the activity of tissue antioxidant enzymes and conventional and immunohistochemical analysis of liver samples were studied for each group. RESULTS: Serum albumin, total protein, fibrinogen levels decreased and prothrombin time was prolonged in the bile duct ligated and transected experimental group but not in the IGF-I treated rats compared with the rats in sham group. Liver malondialdehyde levels significantly increased in control group but not in IGF-1 treated groups. The activities of antioxidant enzymes were decreased compared with the other groups. Histopathology findings of liver biopsy demonstrated intense degree fibrosis and overexpression of fibroblast growth factor and desmin in the control group but a lesser degree of those in the IGF-1 treated groups. CONCLUSIONS: IGF-1 treatment improves liver function and decreases oxidative liver damage and histopathological findings. Further studies are required to delineate the mechanisms of protective effects of IGF-1.

Animals↗
PubMed1997

Ultrasonography, biochemical and hematological profiles in liver disease caused by intravenous administration of dimethylnitrosamine in dogs.

The results of liver function tests and ultrasonographical findings were analysed in 7 dogs that were intravenously injected dimethylnitrosamine (DMNA 2 mg/kg body weight) on 2 consecutive days each week for 10 weeks. Typical clinical signs and similar changes in liver enzyme concentrations that develop in dogs with natural cirrhosis were observed in this canine model. Severe anaemia and a significant reduction in the platelet numbers occurred in the dogs that died in the 5th week, while in all the other dogs these parameters decreased slightly. Serum total protein and the albumin/globulin ratio decreased gradually while the alkaline phosphatase, alanine amino transferase, aspartate amino transferase and gamma glutamyl transpeptidase activities increased significantly (p < 0.05) in all dogs after beginning the administration of DMNA. Ultrasound findings of a coarsened and heterogeneous echo pattern with increased echogenicity that are characteristic of canine cirrhosis were noticed at the same time when the changes in liver enzymes became evident. Present results suggest that ultrasonography in conjunction with liver function tests may be useful in the evaluation of experimentally induced liver cirrhosis.

Alanine Transaminase↗
PubMed1996

Increased hepatic endothelin-1 levels and endothelin receptor density in cirrhotic rats.

Endothelin-1 (ET-1), the most powerful agent to cause constriction of the hepatic vasculature, is synthesized in the liver by sinusoidal endothelial cells. Circulating ET-1 levels have been shown to increase in liver cirrhosis. As liver could be a major source of increased plasma ET-1 as well as a target for its pathologic actions, this study was designed to determine hepatic ET-1 and ET receptor(s) in experimental liver cirrhosis. Cirrhosis was induced in rats by intraperitoneal administration of carbon tetrachloride for 8 weeks. Hepatic ET-1 was measured by radioimmunoassay and ET receptors were determined by radioligand competition binding procedure. A four fold increase in ET-1 concentration accompanied by a 65% increase in ET-receptor density was observed in the cirrhotic liver. There was no change in the ET receptor affinity. The capacity of the liver to metabolize ET-1 was reduced significantly in cirrhosis. Interestingly, transforming growth factor-beta, hepatic levels of which increase in cirrhosis, stimulated ET-1 synthesis in cultured Ito cells. It has been shown that ET-1 is a potent constrictor of Ito cells that proliferate and transform into highly contractile myofibroblasts in liver cirrhosis. Thus, interactions between ET-1 and Ito cells may have significant implications in the pathogenesis and complications of liver cirrhosis.

Animals↗
PubMed1997

Atrial natriuretic peptide: renal effects in cirrhosis of the liver.

Atrial natriuretic peptide is one of a family of natriuretic peptides thought to play a role in the altered sodium balance of advanced liver disease and ascites. Its level is usually increased in the plasma of cirrhotic patients, probably due to relative plasma volume expansion. When exogenous ANP is administered intravenously to dogs or rats with experimental liver cirrhosis and ascites, an heterogeneous natriuretic response is obtained with about half of the population not responding. Similar observations are recorded for patients with clinical cirrhosis. In dogs, attenuation of the ANP-induced natriuresis may depend on a reduction in renal cortical bradykinin activity. In patients with cirrhosis, the ability to release ANP in response to central volume expansion is dissociated from the accompanying natriuresis. Attenuation of the renal tubular response to ANP in this setting may be correlated to the degree of intrahepatic sinusoidal hypertension and associated augmented reflex sympathetic nervous activity to the kidneys. Actual tubular resistance to ANP may be due to reduced Na+ delivery to the inner medullary collecting duct and/or increased degradation of cyclic guanosine monophosphate.

Animals↗