Rat Model Of Hepatic Cirrhosis Research Articles

Peroxisome proliferator-activated receptor-γ doesn't modify altered electrophysiological properties of the CA1 pyramidal neurons in a rat model of hepatic cirrhosis.

Regarding the low quality of life due to the cognitive complications in the patients with hepatic cirrhosis (HC), the goal of this study was to examine the possible neuroprotective effect of pioglitazone (PIO) on the electrophysiological alterations of hippocampus, a major area of cognition, in the experimental model of bile duct ligation (BDL). We used adult male Wistar rats in the present study to perform BDL or sham surgery. Pioglitazone was administered in BDL rats two weeks after the surgery for the next continuous four weeks. The effects of pioglitazone on BDL-induced electrophysiological alterations of the CA1 pyramidal neurons in the hippocampus were evaluated by whole-cell patch clamp recordings. Our findings demonstrated that chronic administration of PIO could not reverse the electrophysiological changes in the CA1 pyramidal neurons of the hippocampus in BDL rats but could improve the hepatic dysfunction.Together, the results of this study suggest that PIO administration cannot counteract altered intrinsic properties of the hippocampal neurons which has been shown recently as an involved mechanism of the cognitive impairments in hepatic encephalopathy (HE).

Comparison of pulsed and oscillating gradient diffusion-weighted MRI for characterizing hepatocellular nodules in liver cirrhosis: ex vivo study in a rat model.

In contrast to classical pulsed gradient diffusion-weighted MRI, oscillating gradient diffusion-weighted MR imaging (DWI) is sensitive to short distance diffusion changes at the intracellular level. To compare the diagnostic performance of pulsed and oscillating DWI for characterizing hepatocellular nodules in a rat model of hepatic cirrhosis. Prospective, experimental study. Cirrhosis was induced by weekly intraperitoneal injection of diethylnitrosamine in Wistar rats. Ex vivo liver MRI was performed at 7T with T1 -weighted, T2 -weighted, pulsed, and oscillating gradient diffusion-weighted sequences. Apparent diffusion coefficient from pulsed (ADCpulsed ) and oscillating gradient (ADCoscillating ) sequences was calculated in 82 nodules identified on the T1 /T2 -weighted images and on pathological examination. Two pathologists classified the nodules in three categories: benign (regenerative and low-grade dysplastic nodules), with intermediate malignancy (high-grade dysplastic nodules and early hepatocellular carcinomas) and overtly malignant (progressed hepatocellular carcinomas). Differences between groups were assessed with Kruskal-Wallis and Mann-Whitney tests. ADC, mainly ADCoscillating , increased in the group of nodules with intermediate malignancy (ADCpulsed : 0.75 ± 0.25 × 10-3 mm2 /s vs. 0.64 ± 0.07 × 10-3 mm2 /s in benign nodules, P = 0.025; ADCoscillating : 0.81 ± 0.20 × 10-3 mm2 /s vs. 0.65 ± 0.13 × 10-3 mm2 /s, P = 0.0008) and ADCpulsed decreased in the group of progressed hepatocellular carcinomas (ADCpulsed : 0.60 ± 0.08 × 10-3 mm2 /s, P = 0.042; ADCoscillating : 0.68 ± 0.08 × 10-3 mm2 /s, P = 0.1). ADC during hepatocarcinogenesis in rats increased in nodules with intermediate malignancy and decreased in progressed hepatocellular carcinomas. Our results suggest that oscillating gradient DWI is more sensitive to the early steps of hepatocarcinogenesis and might be useful for differentiating between high-grade dysplastic nodules / early hepatocellular carcinomas and regenerating nodules / low-grade dysplastic nodules. 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:1065-1074.

Tracking iron oxide labelled mesenchymal stem cells(MSCs) using magnetic resonance imaging (MRI) in a rat model of hepatic cirrhosis.

Homing and tumor attenuation potential of BM-MSCs labelled with superparamagnetic iron-oxide nanoparticles (SPIONs) in a rat model of hepatic cirrhosis was evaluated. Rat BM-MSCs were derived, characterized and labelled with SPIONs (200 nm; 25 mg Fe/ml). Hepatic cirrhosis was induced in Wistar rats (n=30; 10/group) with carbon tetrachloride (CCl4; 0.3 mL/kg body weight) injected twice a week for 12 weeks. Group-I was administered vehicle (castor-oil) alone; Group-II received two doses of unlabelled BM-MSCs (3x106 cells) and Group-III received two doses of SPIONs labelled BM-MSCs (3x106 cells) via tail vein injection (0.5 ml) at weekly intervals. All animals were sacrificed after two weeks for histological, radiological and biochemical analysis. Derived BM-MSCs demonstrated MSCs related CD markers. Histology confirmed induction of hepatic cirrhosis with CCL4. Levels of alanine-aminotransferase, aspartate-aminotransferase,alkaline-phosphatase and gamma glutamyl-transferase returned to normal levels following treatment with BM-MSCs. Uptake and homing of SPIONs labelled BM-MSCs, and reduction in the size of cirrhotic nodules were confirmed using transmission electron microscopy and magnetic resonance imaging respectively. BM-MSCs reduced the pathological effects of CCL4 induced hepatic cirrhosis and labelling BMMSCs with SPIONs were non-toxic and enabled efficient tracking using non-invasive methods.

Effects of Taohongsiwu decoction on the expression of α-SMA and TGF-β1 mRNA in the liver tissues of a rat model of hepatic cirrhosis.

The present study aimed to explore the treatment effects of Taohongsiwu decoction on the liver fibrosis in a rat model, as few prior studies have investigated the anti-fibrotic effects of Taohongsiwu decoction. High-performance liquid chromatography was used to measure the concentration of ferulic acid and hydrosafflower flavin A in the decoction. Male Sprague-Dawley rats were randomly divided into control, model, colchicine (positive group), Taohongsiwu-high, Taohongsiwu-moderate and Taohongsiwu-low groups; 50% carbon tetrachloride (CCl4) of peanut oil solution was subcutaneously injected to the rats except for the control group, and the drugs were intragastrically administered (10 ml/kg) starting at week 7 for 6 continuous weeks. The rats were deprived of food but not water for 12 h following the final administration, then blood was collected from the abdominal aorta. The liver tissues were obtained, fixed with 10% neutral formaldehyde, and embedded with paraffin. The concentrations of ferulic acid and hydroxysafflor flavin A in Taohongsiwu decoction were 0.12 and 0.57 mg/ml, respectively. The three groups treated with Taohongsiwu decoction were found with significantly lower serum levels of aspartate aminotransferase, alanine amino transferase, collagen IV and hyaluronic acid, as well as higher level of albumin (ALB); in addition, the expression levels of α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) mRNA and collagen I were significantly downregulated. Taohongsiwu decoction improved the liver function, reduced the collagen deposition in the serum and liver tissues, and inhibited the expression of α-SMA and TGF-β1.

Characterization of the CA1 pyramidal neurons in rat model of hepatic cirrhosis: insights into their electrophysiological properties.

Although the key contributors of altering neurological function in hepatic encephalopathy are relatively well known, the electrophysiological mechanism of CA1 damage, a key vulnerable area during hyperammonemia, have not yet been defined. Therefore, here we focus on the electrophysiological mechanisms of cognitive impairments following bile duct ligation (BDL). We performed patch-clamp recordings from the CA1 pyramidal neurons in hippocampus of male Wistar rats, which underwent sham or BDL surgery. A striking electrophysiological change of hippocampal neurons in experimental model of BDL was observed in the present study. Spontaneous firing frequency and rate of action potential (AP) rebound was decreased and afterhyperpolarization amplitude (AHP) was increased significantly in hippocampal cells of BDL animals compared to sham group. Together, the results suggest that altered intrinsic properties of the hippocampal neurons may contribute to the cognitive abnormalities during hepatic encephalopathy (HE), highlighting the electrophysiological mechanisms for providing new treatments against HE.

Carvedilol suppresses circulating and hepatic IL-6 responsible for hepatocarcinogenesis of chronically damaged liver in rats

Carvedilol is an anti-oxidant non-selective β-blocker used for reduction of portal blood pressure, prophylaxis of esophageal varices development and bleeding in chronic liver diseases. Recently, it exhibited potent anti-inflammatory, anti-fibrotic, anti-proliferative and anti-carcinogenic effects. In the present study, we evaluated the possible suppressive effect of carvedilol on circulating and hepatic IL-6 levels responsible for hepatocarcinogenesis in a rat model of hepatic cirrhosis. Besides, its effect on hepatic STAT-3 levels, function tests, oxidative stress markers, and hydroxyproline content, hepatic tissue histopathological changes and immunohistochemical expression of E & N-cadherin. Nine-week-old male Wistar rats injected intraperitoneal by 1ml/kg 10% CCL4 in olive oil three times/week (every other day) for 12weeks to induce hepatic cirrhosis. Carvedilol (10mg/kg/day suspended in 0.5% CMC orally), silymarin (50mg/kg/day suspended in 0.5% CMC orally) or combination of both used to treat hepatic cirrhosis from 15th to 84th day. Our data showed that carvedilol and silymarin co-treatment each alone or in combination efficiently reduced the elevated serum IL-6, ALT, AST, ALP and BIL, hepatic IL-6, STAT-3, MDA levels and hydroxyproline content. In addition, it elevated the reduced serum ALB level, hepatic CAT activity and GSH level. Meanwhile, it apparently restored the normal hepatic architecture, collagen distribution and immunohistochemical E & N-cadherin expression. Furthermore, carvedilol was superior to silymarin in improving MDA level. Moreover, the combination of carvedilol and silymarin showed an upper hand in amelioration of the CCL4 induced hepatotoxicity than each alone. Therefore, carvedilol could be promising in prevention of hepatocarcinogenesis in chronic hepatic injuries.

Mesenchymal Stem Cells with Enhanced Bcl-2 Expression Promote Liver Recovery in a Rat Model of Hepatic Cirrhosis

Background/Aims: Mesenchymal stem cell (MSC) transplantation has emerged as an option for the treatment of chronic hepatic cirrhosis, while its therapeutic efficacy could be improved. The bcl-2 gene is anti-apoptotic and can help cell survival and proliferation. Therefore, we explored whether transplanted MSCs with enhanced bcl-2 expression may be beneficial in the treatment of experimental cirrhosis in rats. Methods: MSCs were isolated from rat bone marrow, expanded in vitro and transfected with adeno-associated virus (AAV) engineered the bcl-2 gene (AAV-bcl-2). Rats with cirrhosis induced by carbon tetrachloride (CCl₄) were treated with AAV-bcl-2 infected BMSCs-AAV-bcl-2, with the cells traced in vivo post transplantation. Liver pathology and function were evaluated 7, 14, 21, and 28 days post transplantation, respectively. Results: On day 7 post transplantation, the infused AAV-bcl-2 had integrated into the hepatocyte-like cells (HLCs) that expressed albumin (ALB), Cytokeratin 18 (CK18), and hepatocytes nuclear factor 4a (HNF4a). On day 28 post transplantation, rats in the cirrhosis + BMSCs-AAV-bcl-2 group showed the most dense HLCs, highest mRNA and protein levels of ALB, CK18, and HNF4a, compared to the other groups. Their liver function recovered most rapidly in 4 week observation, while histological sign of cirrhosis remained at the end of this period. Conclusion: BMSCs over expressing bcl-2 gene showed better survival, and enhanced the differentiation into hepatocytes-like cells, and appeared to promote the recovery of liver function in rats with experimental cirrhosis.

Alterations in the intrinsic electrophysiological properties of Purkinje neurons in a rat model of hepatic encephalopathy: Relative preventing effect of PPARγ agonist.

Patients suffering from hepatic cirrhosis (HC) have been shown to have motor and cognitive impairments. The cerebellum, which controls coordinated and rapid movements, is a potential target for the deleterious effects of hyperammonemia induced by bile duct ligation. Therefore, the aim of this study was to determine the mechanisms of motor impairments observed in a rat model of HC and second objective of the current study was to evaluate the possible protective effect of pioglitazone (PIO) on these impairments. Male Wistar rats were used in the current study. Bile duct ligation (BDL) surgery was performed and pioglitazone administration was started two weeks after the surgery for the next four weeks. The effects of pioglitazone on BDL-induced electrophysiological changes of the Purkinje cerebellum neurons were evaluated by Whole-cell patch clamp recordings. Purkinje neurons from the BDL group exhibited significant changes in a number of electrophysiological properties and some alterations partially were counteracted by activation of peroxisome proliferator-activated receptor-γ. Purkinje cells from BDL groups showed a significant increase in the spontaneous firing frequency followed by a decrease in the action potential duration of half-amplitude and spike interval. Chronic administration of pioglitazone could contract this effect of BDL on event frequency and interevent interval, though the difference with the sham group was still significant in the duration of action potential. Results of the current study raise the possibility that BDL may profoundly affect the intrinsic membrane properties of the cerebellar Purkinje neurons and PIO administration can counteract some of these effects.

Erythropoietin ameliorates the motor and cognitive function impairments in a rat model of hepatic cirrhosis

Hepatic encephalopathy (HE) is a serious consequence of hepatic cirrhosis (HC). Previous studies have demonstrated cognitive impairments in both clinical and animal experiments of HC. Some potential therapeutic agents have been used to alleviate the cognitive symptoms in the animal models of HC. In the current study, the possible effect of erythropoietin (ERY) as a potent neuroprotective agent on motor and cognitive impairments induced by HC has been studied. Male Wistar rats (180-200 g) underwent bile duct ligation (BDL) or sham surgery. Administration of ERY (5,000 IU/kg, i.p., daily for three days) was initiated 2 weeks after surgery and lasted for the next 28 days. Open field, rotarod, Morris water maze and passive avoidance learning was used to evaluate the motor and cognitive function of the animals. ANOVA and repeated measures ANOVA were used to analyze the data. p < 0.05 was considered statistically significant. BDL rats had an increased level of hepatic enzymes and bilirubin. Impairment of balance function by BDL was reversed by ERY. Spatial and passive avoidance learning impairments observed in BDL rats were also reversed by chronic administration of ERY. ERY can be offered as a potential neuroprotective agent in the treatment of patients with HC that manifest mental dysfunctions. Though further studies are needed to clarify the exact mechanisms, the neuroprotective properties of ERY against BDL impairments were demonstrated in the current study.

Gene expression profile changes induced upon umbilical cord mesenchymal cell infusion therapy in a rat model of hepatic cirrhosis

To investigate changes in gene expression that occur upon treatment with human umbilical cord mesenchymal stem cells (UC-MSCs) for hepatic cirrhosis using a rat model system. Hepatic cirrhosis was induced in Sprague-Dawley rats by subcutaneous injection of carbon tetrachloride and oral administration of alcohol.UC-MSCs were isolated from human umbilical cord and the cells' immunophenotype and differentiation towards osteogenic and adipogenic lineages were confirmed.The UC-MSC sample or vehicle alone (phosphate buffered saline, PBS) was transplanted by intravenous injection.Histopathological staining and serological testing were used to compare the liver morphology and function among the different groups.The gene expression in the PBS group and UC-MSC group were detected by gene microarray and differences between the groups were statistically analyzed by t-test. Transplantation of the UC-MSCs improved liver function in the hepatic cirrhosis rats.Comparison of the gene expression profiles of the PBS group and the UC-MSC group showed that the latter had up-regulation of the genes related to the complement and coagulation cascades and down-regulation of the genes related to cell proliferation, cell cycle, and collagen synthesis. UC-MSC therapy might improve liver function in cirrhosis by increasing the expression of genes related to the complement and coagulation cascades and by decreasing genes involved in cell proliferation and collagen deposition.

Peroxisome proliferator-activated receptor-γ activation attenuates motor and cognition impairments induced by bile duct ligation in a rat model of hepatic cirrhosis

IntroductionHepatic cirrhosis (HC) is a common health problem with long-term consequences. Patients suffering from HC have been shown to have mental and cognitive impairments. Animal models of HC also confirm such impairments. The objective of the current study was to evaluate the possible protective effect of pioglitazone on these impairments in a rat model of HC. Methods and materialMale Wistar rats were used for the current study. Bile duct ligation (BDL) surgery was performed and pioglitazone (20mg/kg, i.p., once a day) or saline administration was started two weeks after surgery for the next four weeks. Spatial learning (Morris water maze), passive avoidance (PA) learning (shuttle box), balance (rotarod) and muscle strength were evaluated in BDL and sham rats receiving pioglitazone or saline. ResultsBDL rats had an increased level of hepatic enzymes and bilirubin. The increase in hepatic enzymes but not bilirubin by BDL was reversed by pioglitazone. BDL rats showed significant decrease in spatial learning which was reversed by pioglitazone. PA learning was also impaired in BDL rats compared to the other three groups; treatment with pioglitazone reversed these impairments in BDL rats. Balance on the rod was significantly reduced in the BDL and BDL+pioglitazone groups compared to the sham and sham+pioglitazone groups. Muscle strength was not altered in the BDL rats compared to the other two groups. ConclusionResults of the current study confirm previous findings regarding the deleterious effect of BDL on cognitive function. Pioglitazone showed promising results against cognitive impairments. Unchanged locomotion indicates that differences observed in spatial and PA learning are not due to motor deficits.

Pharmacokinetics of diaspirin cross-linked haemoglobin in a rat model of hepatic cirrhosis.

The aim of the study was to evaluate the effect of cirrhosis on the disposition of the haemoglobin-based oxygen carrier, diaspirin cross-linked haemoglobin (DCLHb). Cirrhosis was induced in male Sprague-Dawley rats (200-250 g) by inhalational exposure to carbon tetrachloride (CCl4), over a period of 6 weeks. Pharmacokinetic evaluation was performed after a single intravenous bolus administration of DCLHb (400 mg kg(-1)). Serum biochemistry, including aspartate transaminase, alkaline phosphatase, bile acids, serum albumin, and serum creatinine, were measured in CCl4-treated (n = 6) and age-matched control (n = 6) rats. After 6 weeks, the jugular vein and carotid artery were cannulated for bolus DCLHb administration (400 mg kg(-1)) and blood sampling, respectively, in both groups of rats. Cirrhosis produced significant (P < 0.05) elevations in alkaline phosphatase (497.4 +/- 84.8 U L(-1) vs 241.2 +/- 5.1 U L(-1)), aspartate transaminase (920.5 +/- 190.9 U L(-1) vs 238.2 +/- 118.1 U L(-1)) and bile acids (333.8 +/- 77.3 mg dL(-1) vs 43.8 +/- 4.2 mg dL(-1)) compared with the control group. No significant renal dysfunction was observed as a result of CCl4 exposure. Plasma DCLHb concentrations declined approximately log-linearly. Systemic clearance of DCLHb was estimated to be 2.2 +/- 0.7 mL h(-1) in the treatment group and was slightly, but not significantly, less in the control group (3.6 +/- 1.7 mL h(-1)). There was also a trend toward a longer elimination half-life in the treatment group (4.7 +/- 2.2 h) compared with the control group (3.8 +/- 0.8 h), although this difference was not statistically significant. Cirrhosis does not significantly alter the disposition of DCLHb perhaps due to increased extra-hepatic metabolism by the reticulo-endothelial system.

Therapeutic effect of adipose tissue-derived mesenchymal stem cells transplantation for rat model of hepatic cirrhosis

Therapeutic effect of adipose tissue-derived mesenchymal stem cells transplantation for rat model of hepatic cirrhosis

Splanchnic haemodynamics and vasoactive agents in experimental cirrhosis.

It is well known that portal hypertension is associated with a hyperdynamic systemic circulatory state. This study measures systemic and splanchnic haemodynamics in an experimental rat model of hepatic cirrhosis. It also investigates the association between haemodynamic changes in cirrhotic animals and circulating levels of the vasoactive hormones glucagon and vasoactive intestinal polypeptide (VIP). Splanchnic blood flow was significantly increased in the cirrhotic group (13.2 ± 1.3 vs. 9.2 ± 1.6 ml/min, P < 0.05). Circulating levels of glucagon and VIP were two and five fold increased respectively in cirrhotic animals compared to controls. There was a strong correlation between portal pressure and glucagon levels in the cirrhotic group (r = 0.85). Raised splanchnic blood flow is partly responsible for elevated portal pressure in this model and this rise may be humorally mediated.

A study of regional gastric mucosal blood flow in a rat model of hepatic cirrhosis.

There is controversy surrounding the effects of portal hypertension on the level of perfusion to the gastric wall. This study maps the regional distribution of gastric mucosal and muscle blood flow measured using quantitative autoradiography in a carbon tetrachloride-induced rat model of hepatic cirrhosis. There was a significant increase in both corpus mucosal (124.3 +/- 13.8 vs. 84.8 +/- 4.2 ml.100 g-1.min-1) and muscle blood flow (50.9 +/- 3.6 vs. 33.4 +/- 2.3 ml.100 g-1.min-1) in animals with experimental cirrhosis compared with controls. There was no significant difference in the ratio of blood tracer concentration between the basal and luminal aspects of corpus mucosa in cirrhotic and control groups. We conclude that experimental cirrhosis is associated with gastric mucosal hyperperfusion and that "active" rather than "passive" congestion of the stomach wall may be a more appropriate description of the basic hemodynamic change in this model.