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PubMed1985

Changes in quantitative measures of hepatic function after 90% hepatectomy in rats.

Quantitative measures of liver functions were investigated in rats up to 360 h after 90% hepatectomy and related to total hepatic DNA. Galactose elimination capacity (cytosolic phosphorylation of carbohydrate), p-nitro-anisole demethylase activity (endoplasmic drug hydroxylation) and prothrombin index (protein synthesis at rough endoplasmic membranes) were initially reduced as much as the liver weight, but recovered differently. During hepatic regeneration prothrombin index and galactose elimination were back to control values after an interval of 360 h, while p-nitro-anisole demethylase activity was about 0.4 times control value after that interval. The correlation between total hepatic DNA and liver weight, and between total hepatic protein and liver weight was 0.92 in both cases, indicating their close relationship during hepatic regeneration. Compared to earlier studies on 70% hepatectomy the recovery of metabolic functions after 90% hepatectomy is delayed, as compared to regeneration of total hepatic DNA. The compensatory hyperfunction observed after 70% hepatectomy was not found after 90% hepatectomy, indicating a lost ability to hyperfunction when hepatic function is reduced close to the minimal residual function. This is suggested to be important for the sudden onset of hepatic insufficiency.

Animals↗
PubMed1986

Hepatic regeneration and metabolism after partial hepatectomy in normal rats: effects of insulin therapy.

The effect of insulin therapy on liver regeneration has been studied in normal fed rats 12, 24 and 48 h after partial hepatectomy. Dry weight of regenerating liver increased between 12 and 48 h after partial hepatectomy and was unaffected by insulin therapy. [6-3H] Thymidine uptake peaked at 24-h (24.7 +/- 2.4% of total liver cells) and insulin treatment had no additional effect. At 12-h after partial hepatectomy, hepatic [ATP] was decreased 15%, while [ADP] and [AMP] were increased 47% and 83% respectively compared with sham-operated animals. Partial hepatectomy also caused an increase in hepatic [triglyceride], a decrease in hepatic [glycogen] and an increase in the levels of glucose and several glycolytic intermediates. The hepatic redox ratios, [lactate]:[pyruvate] and [3-hydroxybutyrate]:[acetoacetate], were elevated. Insulin therapy had only minor effects on hepatic adenine nucleotide levels, intermediary metabolite concentrations or intrahepatic redox ratios after partial hepatectomy. These findings suggest a decreased hepatic intracellular energy state in regenerating liver; insulin therapy in normal rats does not influence this metabolic change nor the regenerative response.

Adenine Nucleotides↗
PubMedDate not supplied

Endotoxin affects the expansion modes of liver macrophages after partial hepatectomy.

We studied the effect of increased endotoxin levels on the expansion modes of liver macrophages after two-thirds partial hepatectomy using anti-endotoxin polymyxin B. The expansion consists of dual modes: local proliferation and immigration. Local proliferation of mature cells was evaluated by the S-phase proportion measured by flow cytometric DNA analysis. This proportion (11.8 +/- 1.3% before hepatectomy) decreased to 6.0 +/- 1.1% at 12 h and reached a maximum of 21.9 +/- 2.7% on the 5th day after hepatectomy. In polymyxin B treated rats, the proportion reached a maximum of 21.1 +/- 1.6% at 48 h without any preceding decrease. Immigration of macrophage precursors was evaluated by the decreasing proportion of latex beads-containing cells that were marked as resident liver macrophages by injection of latex beads before hepatectomy. This proportion (98.7 +/- 0.2% before hepatectomy) was significantly decreased to 90.5 +/- 1.6% at 48 h. In polymyxin B treated rats, however, the proportion showed no significant decrease within 3 days. These results indicate that endogenous endotoxin, which suppresses the local proliferation and promotes extrahepatic recruitment, regulates the number of liver macrophages in regenerating rat liver.

Animals↗
PubMed1994

Effects of total hepatectomy: studies in a porcine model.

The effects of total hepatectomy in a porcine model were studied. A portacaval shunt was constructed prior to hepatectomy, and the excised segment of inferior vena cava was replaced with a Dacron graft as soon as the liver had been removed. While the vena cava was clamped, venous return from the lower body to the heart was maintained using an extracorporeal veno-venous bypass system. The results of the study revealed that surprisingly few haemodynamic, biochemical or coagulation disturbances occur within the first 5 h following total hepatectomy in the pig, an animal with remarkably close anatomical and physiological similarities to man. In the anhepatic period which follows total hepatectomy during clinical liver transplantation, the situation is more complex, because pre-existing liver disease and portal hypertension, as well as major blood loss, often provide other reasons for metabolic and haemodynamic instability and coagulation disorders. The possible relevance of the findings in this large animal model to events that occur following total hepatectomy in the clinical situation is discussed.

Alkaline Phosphatase↗
PubMed2006

Ischemic preconditioning improves liver regeneration by sustaining energy metabolism after partial hepatectomy under ischemia in rats.

BACKGROUND: The protective effect of ischemic preconditioning (IPC) has been reported on improvement of survival, reduction of liver necrosis and enhancement of the regenerative capacity of hepatocytes after partial hepatectomy. This study was undertaken to confirm that IPC has a significant impact on regeneration of hepatocytes after partial hepatectomy in ischemically damaged liver. In addition, we sought to examine the role of adenine nucleotides in this process. METHODS: Wistar rats were subjected to 60 min of total hepatic ischemia, followed by 70% hepatectomy. The animals were subdivided into an IPC (10/15 min) group and a non-IPC (control) group. Liver function tests and arginase activity were analyzed. Hepatic adenosine triphosphate (ATP), adenosine diphosphate and adenosine monophosphate were measured using gradient high-performance liquid chromatography. The liver regeneration was identified using relative liver weight and proliferating cell nuclear antigen (PCNA) labeling index. RESULTS: IPC treatment improved serum liver enzymes and tissue arginase activity (P<0.05) when compared with the control group. The preconditioned livers were associated with upregulation of ATP expression and also increased tissue energy charge. Regenerated liver weight in the IPC group was significantly higher than in the control group (P<0.05). The PCNA labeling index in the remnant livers in the IPC group was also significantly increased at 24 and 48 h after partial hepatectomy (P<0.05). CONCLUSION: These results suggest that IPC-augmented liver regeneration after hepatectomy, probably due to the stabilization of energy metabolism in rats.

Adenosine Triphosphate↗
PubMed1990

Effect of gastrin on liver regeneration after partial hepatectomy in rats.

Gastrin has been shown to be an important trophic hormone for the mucosa of the stomach and the proximal intestine. In the present study the effect of gastrin on liver regeneration after partial hepatectomy in rats was investigated. After partial hepatectomy a significant rise in the concentration of gastrin in portal venous blood was found six, 12, and 18 hours after 70% hepatectomy. The effect of changes in the endogenous gastrin concentration on the liver regeneration was investigated in rats subjected to antrectomy or to fundectomy. Partial hepatectomy was done three weeks after the primary surgery. We found antrectomy to decrease liver regeneration, whereas fundectomy had no effect. Administration of pentagastrin 300 micrograms/kg sc three times daily for two and four days after partial hepatectomy significantly increased the rate of liver regeneration compared with controls. This study suggests that gastrin has a hepatotrophic effect. Whether this effect is caused by a direct action of gastrin on the hepatocytes or it is an indirect effect mediated by for instance insulin, glucagon or epidermal growth factor has to be further investigated.

Animals↗
PubMed2000

Beneficial effects of prostaglandin E(1) incorporated in lipid microspheres on liver injury and regeneration after 90% partial hepatectomy in rats.

The aim of this study was to assess how the administration of prostaglandin E(1) incorporated in lipid microspheres (Lipo PGE(1)) affects liver injury and regeneration after massive hepatectomy in rats. Two hundred and eight male Wistar rats underwent 90% partial hepatectomy. Lipo PGE(1) of 1, 10 or 30 microg/kg were administered intraperitoneally at 6 h prior to and 0 and 6 h after hepatectomy. Postoperative increases in serum GOT, total bilirubin, IL-6 and plasma endotoxin levels were significantly suppressed by Lipo PGE(1). The depressed phagocytic index and arterial ketone body ratio and hepatic DNA synthesis after 90% partial hepatectomy were significantly enhanced by Lipo PGE(1), which resulted in the improvement of survival. Lipo PGE(1) might bring about a protective effect on liver injury and an enhancement of liver regeneration after massive hepatectomy.

Alprostadil↗
PubMed2001

Expression and role of vascular endothelial growth factor in liver regeneration after partial hepatectomy in rats.

Vascular endothelial growth factor (VEGF) plays a major role in angiogenesis, which is essential for both healing of injured tissue and proliferation of carcinoma cells. In this study we elucidated the expression and role of VEGF in rat liver regeneration after partial hepatectomy. VEGF expression was mainly detected in periportal hepatocytes and reached a maximal level 48-72 hr after partial hepatectomy by both immunohistochemistry and in situ hybridization. Similarly, immunohistochemistry for Ki-67 showed that the proliferative activity of sinusoidal endothelial cells was highest in the periportal area and reached a maximal level 72 hr after partial hepatectomy. Moreover, neutralization of VEGF significantly inhibited proliferative activity of hepatocytes (p<0. 0001), as well as sinusoidal endothelial cells (p<0.001), at 48 and 96 hr after partial hepatectomy. Conversely, injection of VEGF significantly promoted proliferative activity of hepatocytes (p<0. 0001) as well as sinusoidal endothelial cells (p<0.0005) at 48 hr after partial hepatectomy. These results suggest that VEGF promotes proliferation of hepatocytes through reconstruction of liver sinusoids by proliferation of sinusoidal endothelial cells. Furthermore, these data point to a new therapeutic strategy, the use of VEGF and other hepatocyte growth factors in fulminant or severe acute hepatitis.

Animals↗
PubMedDate not supplied

Analysis of host response to hepatectomy by simultaneous measurement of cytokines in the portal vein, caval vein and radial artery.

We analysed the host response to hepatectomy by simultaneous measurement of various cytokines and their antagonists in the portal vein, caval vein and radial artery in 10 patients with hepatocellular carcinoma. Concentrations of tumour necrosis factor-alpha (TNF), interleukin (IL) 1 beta, IL-2, IL-6, IL-10, soluble TNF receptor type I (sTNF-R), soluble IL-2 receptor (sIL-2R), IL-1 receptor antagonist (IL-1ra), soluble CD14 (sCD14) and endotoxin were determined just before and 1 h after hepatectomy. The values of IL-6, sTNF-R and IL-1ra were significantly increased after hepatectomy at each sampling site. In contrast, the levels of sIL-2R and sCD14 after hepatectomy were significantly decreased, and the levels of IL-1 beta, IL-2 and IL-10 were below the detection limits. Differences in cytokine concentrations between sampling sites revealed that the surgical stress of hepatectomy induced significant IL-1ra production in the liver and sTNF-R and IL-6 production in the lungs. These results suggest that hepatic resection is followed by the production of cytokine antagonists, such as IL-1ra, sTNF-R and IL-6, which could represent an important regulatory mechanism against surgical stress.

Aged↗
PubMed2005

The involvement of polyamines as substrates of transglutaminase in zonal different hepatocyte proliferation after partial hepatectomy.

We have recently demonstrated the inverse correlation between transglutaminase (TGase) activity and DNA synthesis in periportal hepatocytes (PPH) and perivenous hepatocytes (PVH) at 1 d after partial hepatectomy. In order to elucidate a role of polyamines as substrates of TGase in the differential growth capacities between PPH and PVH from regenerating liver, we investigated the zonal differences in alteration of ornithine decarboxylase (ODC) activity and polyamines. In two subpopulations, the inverse correlation between DNA synthesis and epsilon-(gamma-glutamyl) lysine (Gln-Lys) cross-linking catalyzed by TGase was demonstrated at 1 d after partial hepatectomy. ODC activity in PPH significantly increased with a peak at 1 d after partial hepatectomy, whereas did not in PVH. Protein-binding SPD in PPH also transiently increased with a peak at 1 d after partial hepatectomy, but did not in PVH. These results suggest that at 1 d after partial hepatectomy, in PPH, the inhibition of Gln-Lys cross-linking by the formation of N-gamma-glutamyl SPD leads to the increase of DNA synthesis, whereas in PVH, enhanced formation of Gln-Lys cross-linking leads to the lower DNA synthesis.

Animals↗
PubMed2006

Partial hepatectomy enhances polyethylenimine-mediated plasmid DNA delivery.

Polyethylenimine (PEI) is widely used for non-viral transfection in vitro and in vivo. Hepatectomy is an interesting and considerable factor modifying PEI-mediated gene expression. We investigated the gene expression in mice over time following partial hepatectomy after an intravenous injection of PEI/plasmid DNA (pDNA) complex. pDNA encoding firefly luciferase was used as the model reporter gene. The hepatectomized liver was rapidly regenerated until 72 h. After 168 h, the liver weight of hepatectomized mice was similar to that of control mice. Slight liver function impairment was only observed at 1-24 h after hepatectomy in alanine aminotransferase and aspartate aminotransferase levels. Luciferase activity in the liver of partial hepatectomized mice at 48 h after partial hepatectomy increased by 70 times compared with that of control mice; however, luciferase activities did not significantly differ between hepatectomized mice and control mice in the spleen, lung, kidney, and heart. Among the lobes, luciferase activity by gram of tissue was not significantly different, indicating that gene expression enhancement by partial hepatectomy occurred equally throughout the liver. In conclusion, our findings demonstrate that liver resection is an influencing factor on PEI-mediated gene delivery in mice. These results indicate the necessity of considering cell division in PEI-mediated pDNA delivery.

Animals↗
PubMed1981

Changes in lipid composition of plasma lipoproteins after total hepatectomy in the rat.

Lipidic composition of plasma lipoproteins were determined at different times after total hepatectomy in the rat and compared with those in sham-operated animals. After hepatectomy there was a progressive decrease in the plasma triglycerides amounts corresponding to changes in the content of very low density lipoproteins (VLDL) triglycerides. Phospholipid concentrations in both low density lipoproteins (LDL) and VLDL decreased after hepatectomy but theses lipids were unchanged in high density lipoproteins (HDL) which are the main contributors to plasma phospholipid content. Contrary to the other lipid components, plasma cholesterol levels increased after hepatectomy, due mainly to the increment in HDL-esterified cholesterol. Modifications in plasma triglyceride levels after hepatectomy are interpreted as the result of total reduced synthesis and the effect of extrahepatic lipoprotein lipase activity on VLDL-triglycerides. Changes in cholesterol are considered due to its enhanced production by extrahepatic tissues.

Animals↗
PubMed2006

Changes in growth factor and cytokine expression in biliary obstructed rat liver and their relationship with delayed liver regeneration after partial hepatectomy.

AIM: To study the effects of obstructive jaundice on liver regeneration after partial hepatectomy. METHODS: Hepatocyte growth factor (HGF), its receptor, c-Met, vascular endothelial growth factor (VEGF) and transforming growth factor-beta1 (TGF-beta1) mRNA expression in both liver tissue and isolated liver cells were investigated after biliary obstruction (BO) by quantitative reverse-transcription polymerase chain reaction (RT-PCR) using a LightCycler. Immunohistochemical staining for desmin and alpha-smooth muscle actin (alpha-SMA) was also studied. Regenerating liver weight and proliferating cell nuclear antigen (PCNA) labeling index, and growth factor expression were then evaluated after 70% hepatectomy with concomitant internal biliary drainage in BO rats or sham-operated rats. RESULTS: Hepatic TGF-beta1 mRNA levels increased significantly 14 days after BO, and further increased with duration of cholestasis. Meanwhile, HGF and VEGF tended to increase, but was not significant. In cell isolates, TGF-beta1 mRNA was found mainly in the hepatic stellate cell (HSC) fraction. Immunohistochemical studies revealed an increased number of HSCs (desmin-positive cells) and activated HSCs (alpha-SMA-positive cells) in portal areas after BO. In a hepatectomy model, liver regeneration was delayed in BO rats, as compared to sham-operated rats. TGF-beta1 mRNA was significantly up-regulated up to 48 h after hepatectomy, and the earlier HGF mRNA peak was lost in BO rats. CONCLUSION: BO induces HSCs proliferation and activation, leading to up-regulation of TGF-beta1 mRNA and suppression of HGF mRNA in livers. These altered expression patterns may be strongly involved in delayed liver regeneration after hepatectomy with obstructive jaundice.

Actins↗
PubMed2006

Expression patterns of cytokine, growth factor and cell cycle-related genes after partial hepatectomy in rats with thioacetamide-induced cirrhosis.

AIM: To examine the differences in the responses of normal and cirrhotic livers to partial hepatectomy in relation to the factors influencing liver regeneration. METHODS: Cirrhosis was induced in rats by administration of thioacetamide. Untreated rats were used as controls. The control rats as well as the cirrhotic rats were subjected to 70% partial hepatectomy. At different time points after hepatectomy, the livers were collected and the levels of cytokines, growth factors and cell cycle proteins were analyzed. RESULTS: After hepatectomy, the cirrhotic remnant expressed significantly lower levels of cyclin D1, its kinase partner, cdk4, and cyclin E as compared to the controls up to 72 h post hepatectomy. Significantly lower levels of cyclin A and cdk2 were also observed while the cdk inhibitor, p27 was significantly higher. In addition, the cirrhotic group had lower IL-6 levels than the control group at all time points up to 72 h following resection. CONCLUSION: The data from our study shows that impaired liver regeneration in cirrhotic remnants is associated with low expression of cyclins and cdks. This might be the consequence of the low IL-6 levels in cirrhotic liver remnant which would in turn influence the actions of transcription factors that regulate genes involved in cell proliferation and metabolic homeostasis during the regeneration process.

Animals↗
PubMed1999

A new technique for total hepatectomy in the pig for testing liver support devices.

BACKGROUND: A large animal model of total hepatectomy is suitable to test the efficacy of any system designed to support patients in hepatic coma. The models previously described in the pig entail a significant degree of surgical trauma, which might alter the evolution of the ensuring hepatic failure and compromise the reproducibility of the model. METHODS: Twenty-eight pigs underwent a total hepatectomy according to a new technique. A model was considered satisfactory when it required no blood transfusions and when hematologic and hemodynamic parameters determined before, during, and until 4 hours after hepatectomy showed no significant variations. Moreover, to revive the pattern of hepatic coma produced in the anhepatic model, 7 pigs were monitored until brain death occurred. RESULTS: Twenty-five pigs (89%) underwent a smooth total hepatectomy with minimal variations of the selected parameters. They constituted a highly homogeneous group. Survival of the 7 pigs, followed up until brain death occurred, ranged from 625 to 1595 minutes (mean 1013.57 minutes). The animals remained stable until a few hours before brain death, an event heralded by a final sharp increase of the serum ammonia level and by a well-evident decline of both arterial pressure and liver-dependent clotting factors. CONCLUSIONS: This technique of total hepatectomy allows the construction of a reproducible model of anhepaty suitable to test the efficacy of any system conceived to temporarily replace hepatic functions.

Anastomosis, Surgical↗
PubMed1999

Functional capacity of the cirrhotic liver after partial hepatectomy in the rat.

BACKGROUND: Posthepatectomy liver insufficiency is one of the most serious problems associated with a major hepatic resection, especially in the cirrhotic liver, which has less functional reserve than the normal liver. Evaluation of morphologic liver regeneration is important in cirrhotic rats, as well as in the normal liver, and assessment of functional capacity in cirrhosis is clinically important for preventing hepatic insufficiency of the remnant liver after hepatectomy. METHODS: We evaluated the functional capacity of the cirrhotic liver induced by carbon tetrachloride in rats and studied the correlation between morphologic and functional restoration of the liver after partial hepatectomy in comparison with healthy rats. Morphologic restoration of the liver after hepatectomy was evaluated on the basis of remnant liver weight, proliferating cell nuclear antigen labeling index, and the DNA content of the regenerating liver. Functional restoration was evaluated by the indocyanine green disappearance rate and serum aminopyrine clearance. RESULTS: Morphologic restoration in cirrhotic rats was delayed in comparison with healthy rats. Although functional capacity in the cirrhotic rats was diminished, functional restoration was advanced after a two-thirds hepatectomy, in comparison with morphologic restoration. CONCLUSIONS: Functional restoration in cirrhotic rats after partial hepatectomy is advanced in comparison with morphologic restoration.

Animals↗
PubMedDate not supplied

Hepatic function immediately after hepatectomy as a significant risk factor for early recurrence in hepatocellular carcinoma.

BACKGROUND/AIMS: The aim of this study was to clarify the significant risk factors as they relate to early recurrence after hepatectomy in cirrhotic patients with hepatocellular carcinoma (HCC). METHODOLOGY: We retrospectively investigated 42 cirrhotic patients undergoing hepatectomy for a single HCC. We compared the clinicopathologic features of 14 patients with early intrahepatic recurrence (recurrence was detected within 1 year after hepatic resection; Group 1) with 28 patients without recurrence or with late intrahepatic recurrence (recurrence was confirmed more than 1 year after hepatic resection; Group 2). RESULTS: There were no significant differences in the pre-operative and intra-operative clinical background data or pathological data between the 2 groups. Regarding recurrence pattern, although not significant, the incidence of intrahepatic metastasis in Group 1 (85.7%) was higher than in Group 2 (50.0%). Maximum values of total bilirubin and albumin within 7 days after hepatectomy for patients in Group 2 were significantly better than those in Group 1. Aspatate aminotransferase (AST) and alanine aminotransferase (ALT) immediately after hepatectomy in Group 1 were also higher than in Group 2, although statistically insignificant. The overall 1-year and 3-year survival rates between Group 1 versus Group 2 were 85.7% versus 100% (p < 0.01) and 57.2% versus 90.0% (p < 0.01), respectively. CONCLUSIONS: Hepatic functional damage immediately after hepatectomy is as significant risk factor for early intrahepatic recurrence in cirrhotic HCC. Careful perioperative management of hepatic function may therefore be important in preventing early recurrence and prolonging survival.

Alanine Transaminase↗
PubMed1998

[The effect of partial hepatectomy and portal vein occlusion on aminopyrine metabolism capacity of the liver in rats].

To observe the variation of metabolic function and anatomical weight of the liver after partial hepatectomy and occlusion of portal branches feeding the same magnitude of the liver lobes, hepatic 14C-aminopyrine demethylation capacity determined by aminopyrine breath test and liver weight in rats were examined and compared in series in this study. The results showed that 14CO2 expiratory clearance rate was reduced by 50% at 2 hours and by 70% at 24 hours after 70% hepatectomy. Then it increased gradually and was similar to the preoperative level in 2 weeks. The remnant liver weight was lowest at 2 hours and increased to 80% of the control in 7 days after 70% hepatectomy. It recovered to normal in 2 weeks. In 90% hepatectomy group, 14CO2 expiratory clearance rate decreased by 90% at 2 hours after operation. Thereafter, all rats died very soon. In the 2 portal vein occlusion groups, 14CO2 expiratory clearance rate had little change at 2 hours and it declined by about 40% at 24 hours after ligation of portal branches feeding 70% or 90% liver mass. It recovered gradually and returned to the preoperative level in 2 weeks. The total liver weight in 2 portal occlusion groups was not significantly different from that in the control except that it was slightly lower than the control at 24 hours after operation. This experimental study suggests that comparing deprivation of portal blood feeding partial liver mass with corresponding partial hepatectomy, the former can not only keep the anatomical liver weight relatively stable but also produce a lesser damage to hepatic metabolic function.

Aminopyrine↗