[Effects of homologous and heterologous liver tissue with adjuvants on the regenerating liver].
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Adjuvants, Immunologic↗
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Expression of MRP2 and MRP3 during liver regeneration after 90% partial hepatectomy in rats.
BACKGROUND: Small-for-size grafts often cause persistent conjugated hyperbilirubinemia in the recipient after adult-to-adult living donor liver transplantation, but the cause has not yet been clarified. In physiologic status, bilirubin is excreted from hepatocytes to the bile canaliculus by means of multidrug resistance protein (MRP) 2 and, in particular circumstances, by means of MRP3 to the sinusoidal space. The aim of this study was to research whether there is any change in bilirubin excretion pattern during liver regeneration with reference to expression of MRP2 and MRP3. METHODS: Sprague-Dawley rats underwent sham operation (n=37), 70% hepatectomy (n=38), or 90% hepatectomy (n=37). The degree of liver regeneration, total and direct bilirubin, protein synthesis, and interleukin (IL)-6 were serially assessed. Expression of MRP2 and MRP3 were semiquantified by Western blotting. RESULTS: The proliferating cell nuclear antigen labeling index indicated rapid liver regeneration after 70% and 90% hepatectomy. Serum levels of total and direct bilirubin increased significantly (P<0.05), and conjugated hyperbilirubinemia was proved only in the 90% hepatectomy group. Coagulation factor VII dipped but increased as early as 12 to 24 hr postoperatively in both hepatectomy groups. Plasma IL-6 levels were significantly increased in the 90% hepatectomy group (P<0.05). Expression of MRP2 was decreased and MRP3 was expressed at 36 and 72 hr postoperatively in the 90% hepatectomy group, whereas no change was observed in MRP expression in the 70% hepatectomy group. CONCLUSIONS: During liver regeneration after critical hepatectomy such as 90% hepatectomy, decrease of MRP2 and expression of MRP3 may play an important role in postoperative hyperbilirubinemia.
Animals↗
Effect of acute ethanol exposure on hepatic stimulator substance (HSS) levels during liver regeneration: protective function of HSS.
Ethanol administration in rats induces liver damage and suppression of liver regeneration. To further understand the underlying mechanism, we investigated the effects of ethanol on hepatic stimulator substance (HSS) levels during liver regeneration caused by partial hepatectomy. The hepatotrophic action of HSS to ethanol-treated partially hepatectomized rats was also examined. Rats received repetitive ethanol or saline doses beginning 1 hr prior to 70% partial hepatectomy (PH), and the animals were killed at 16, 24, 32, 40, 48, and 60 hr after PH. Our results showed that ethanol inhibited hepatic regenerative capacity and prolonged liver regenerative process. HSS biological activity in ethanol-administered rats peaked at 48 hr after PH, in contrast to saline-treated ones where activity peaked at 24 hr. Additionally, exogenous HSS administration to ethanol-treated partially hepatectomized rats increased liver proliferating capacity and suppressed the elevation of serum ALT activity. These results showed that ethanol modifies the time course of HSS biological activity during the regenerating process. The observed suppression of HSS activity at 24 hr after PH was in relation with a reduction of DNA synthesis. Exogenous administration of HSS to ethanol-treated partially hepatectomized rats restored DNA synthesis and ameliorated serum AST levels, indicating that HSS could be used in the treatment of ethanol-induced hepatic failures.
Alanine Transaminase↗
The effect of extrahepatic cholestasis on liver regeneration after partial hepatectomy in the rat.
Liver regeneration after partial hepatectomy was studied in four groups of rats: control rats (n = 12), rats with 1 week of common bile duct obstruction (n = 11), rats with restoration of bile flow after 1 week of obstruction (n = 9) and a sham-operated group (n = 7). Parameters of DNA synthesis--thymidine kinase activity and in vivo bromodeoxyuridine incorporation--were measured at partial hepatectomy (T = 0), and 24 and 48 h after partial hepatectomy. During common bile duct obstruction, DNA synthesis was already stimulated at T = 0, but partial hepatectomy in common bile duct obstruction rats induced a delayed DNA synthesis. After 1 week of restoration of bile flow, normal DNA synthesis had returned at T = 0, but DNA synthesis after partial hepatectomy was still delayed. The sham-operated rats showed a normal regeneration response after partial hepatectomy assessed by bromodeoxyuridine incorporation but delayed as assessed by thymidine kinase activity, partly due to the impaired physical condition of the animals. The present data support the hypothesis that during cholestasis, regeneration promoting, and inhibitory factors accumulate in the liver, their balance determining whether regeneration after partial hepatectomy will occur in a normal, enhanced or delayed way.
Animals↗
[The effect of a chalone-containing fraction on passage of the S-phase of the cell cycle in regenerating liver].
The duration and reversibility of the liver chalone-containing fraction on DNA synthesis in regenerating liver cells have been studied. It has been shown that administration of the [14C] chalone-containing fraction results in a rapid specific binding of the label to liver cells in which the label is retained for no less than 12 hours. The specific radioactivity of DNA in regenerating liver cells decreases 3-4-fold irrespective of the time of administration of the [14C] chalone-containing fraction. After repeated injections of the fraction under study, the hepatocytes loss their sensitivity towards this fraction. It is suggested that chalones exclude some part of the hepatocytes from the cell cycle which, in turn, leads to the asynchronous involvement in the cell cycle of a new hepatocyte population which is resistant to the chalone action.
Animals↗
Contribution of bone marrow cells to liver regeneration after partial hepatectomy in mice.
BACKGROUND/AIMS: We examined whether bone marrow (BM) cells can commit to liver-consisting cells during liver regeneration after partial hepatectomy, using mice transplanted with green fluorescent protein (GFP) positive BM from GFP transgenic mice. METHODS: Partial hepatectomy or sham operation was performed. Lineage marker analysis of GFP positive liver cells was by immunostaining and flow cytometry. DiI-labeled acetylated low-density lipoprotein uptake or microsphere phagocytosis was examined in vitro. Lineage marker expression in BM and peripheral blood (PB) cells, and the vascular endothelial growth factor (VEGF) concentration in the liver were also examined. RESULTS: In hepatectomized mice, significantly more GFP positive cells participated in liver sinusoid than in sham-operated mice, expressing CD31 but not albumin. The percentage of cells that incorporated acetylated low-density lipoprotein but not microspheres was 69.5+/-3.4%, while 28.3+/-2.6% incorporated both, revealing sinusoidal endothelial and Kupffer cells, respectively. Increased expression of the CD31 and CD16/CD32 on GFP positive liver cells was also detected. The elevation of the VEGF concentration during liver regeneration and the increase in the CD34 and Flk-1 expression in the liver, BM, and PB cells suggested endothelial progenitor cell mobilization. CONCLUSIONS: GFP cell-marking provided direct evidence of the BM cells participation in liver regeneration after hepatectomy, where the majority was committed to sinusoidal endothelial cells probably through endothelial progenitor cell mobilization.
Animals↗
Implication of stem cell factor in human liver regeneration after transplantation and resection.
The stem cell factor (SCF), besides regulating hemopoietic stem cells homing and proliferation, has proliferative effects on hepatocytes and may be involved in liver regeneration. We investigate if liver transplantation (LT) and hepatic resection (HR) modify the concentration of soluble SCF (s-SCF) in peripheral blood of 15 LT and 7 HR. s-SCF was measured by ELISA as ng/ml. s-SCF basal levels were higher in LT that in HR (818 +/- 349 vs. 479 +/- 79, p = 0.005). A significant increase of s-SCF, peaking at postoperative day +3, was seen after LT (from 818 +/- 349 to 1212 +/- 461, p = 0.01) and HR (from 479 +/- 79 to 698 +/- 122, p = 0.004). s-SCF peak levels were higher after LT than HR (p = 0.0008). At day +7 s-SCF concentration returned to baseline values. LT have a higher basal s-SCF level than HR. These data show for the first time that liver injury affects s-SCF level and suggest that SCF may be involved also in clinical liver regeneration.
Adult↗
Gap junctions and growth control in liver regeneration and in isolated rat hepatocytes.
The hepatocytes in the mature normal liver are tightly coupled through gap junctions, except during compensatory hyperplasia (regeneration) after partial hepatectomy when the gap junctions become down-regulated. The significance of this down-regulation has been a long-standing enigma. The present study of hepatocytes in primary culture and in the regenerating liver aimed at defining the relationship, if any, between hepatocyte gap junctional communication and proliferation. Gap junctional down-regulation in the regenerating liver appeared to be a specific phenomenon because desmosomes and the surface contact area between neighboring hepatocytes remained constant. All agents and conditions (dexamethasone in vivo; dexamethasone, cyclic adenosine monophosphate, serum, and high cell density in vitro) delaying gap junctional down-regulation also increased the lag before the cells reached competence to enter S phase. This raised the possibility that hepatocyte DNA replication was inhibited through preservation of gap junctions. However, we disproved this assumption by showing that the DNA replication (more specifically the G1/S transition rate constant) was inhibited even in hepatocytes completely devoid of gap junctional communication. The teleological advantage of linking gap junctional down-regulation to hepatocyte G1 progression therefore may not be to trigger DNA replication but to ensure that proliferating hepatocytes and hepatocytes responsible for liver-specific metabolic functions maintain separate pools of metabolites and signaling molecules.
Animals↗
Protective effect of recombinant human augmenter of liver regeneration on CCl4-induced hepatitis in mice.
OBJECTIVE: To observe the anti-injury role of recombinant human augmenter of liver regeneration. METHODS: To establish liver injury models induced by CCl4 in vivo and in vitro, cell survival rates and LDH release rates served as observing index in experiments in vitro. Survival rates of liver failure animals, serum concentration of ALT, LDH, DNA and pathological examination were selected as parameters in experiment in vivo. RESULTS: rhALR could increase the survival rates and decrease the LDH release rates of injured hepatocytes in vitro. rhALR could also increase the survival rates of liver failure animal, promote hepatocyte proliferation and decrease the serum level of ALT and LDH in vivo. CONCLUSION: ALR is an important stimulator for liver regeneration and may play important role in liver damage repair.
Animals↗
Ethanol inhibits liver regeneration in rats without reducing transcripts of key protooncogenes.
The mechanisms responsible for ethanol-associated inhibition of liver regeneration are poorly understood but may involve the modulation of protooncogene expression. To test this hypothesis, the steady-state messenger RNA levels of several protooncogenes involved in cellular proliferation were measured in livers obtained from ethanol-fed rats and isocalorically maintained controls before and during surgically-induced liver regeneration. Regeneration was significantly inhibited in ethanol-fed rats as evidenced by delayed induction of ornithine decarboxylase activity and reduced thymidine incorporation, mitotic index, and restoration of liver mass after partial hepatectomy. As previously reported, partial hepatectomy induced the time-dependent expression of mRNA for c-fos, c-myc, and c-Ha-ras. However, the transcript levels of these protooncogenes were indistinguishable in ethanol and control livers at various time points between 0-72 hours after partial hepatectomy. Although regeneration after partial hepatectomy is significantly delayed in ethanol-fed rats, the transcription of certain protooncogenes, which encode for both DNA-binding and signal-transducing proteins, appears to proceed normally. Consequently, ethanol-associated impairment of liver regeneration cannot be explained by altered transcription of these protooncogenes. The results suggest that either the expression of these protooncogenes alone may not be sufficient to trigger liver regeneration or that ethanol inhibits protooncogene-mediated events at posttranscriptional levels.
Animals↗
Effect of follistatin on rat liver regeneration and tumor growth after portal occlusion.
BACKGROUND/AIMS: Although follistatin is known to be a positive regulator in liver regeneration after hepatectomy, the effects of follistatin on regeneration following portal occlusion and on tumor growth are not known. METHODOLOGY: In experiment 1, rats were injected with follistatin immediately following 70% hepatic resection (HR), ligation of the left portal vein (PVL), or ligation of the left hepatic artery (HAL). Hepatic regenerative activity then was determined. In experiment 2, rats were injected intraportally with AH130 tumor cells. At 7 days after injection, the same procedures were carried out as in experiment 1. In a third experiment, in vitro, AH130 cells were cultured with various concentrations of activin A or follistatin, and cell proliferation was assessed. RESULTS: In experiment 1, follistatin did not accelerate liver regeneration after PVL. In experiment 2, follistatin significantly increased liver weight after HR, but did not accelerate tumor growth in any group. In vitro, neither follistatin nor activin affected proliferation of tumor cells. CONCLUSIONS: The mechanism of liver regeneration after PVL appears to differ from that after HR. Follistatin acts as a growth promoter for hepatocytes, but not for cancer cells.
Activins↗
[11C]choline uptake in regenerating liver after partial hepatectomy or CCl4-administration.
To characterize [methyl-(11)C]choline ([(11)C]choline) as an oncologic PET radiopharmaceutical, [(11)C]choline uptake in regenerating livers after partial hepatectomy as a model of typical proliferating tissue and after CCl(4) insult as that of proliferating tissue with inflammation, was studied in rats. [(11)C]Choline, [(18)F]2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) and [2-(14)C]thymidine ([(14)C]TdR) uptake was studied in regenerating rat liver after 70% partial hepatectomy or CCl(4)-administration. [(11)C]Choline uptake in regenerating liver after partial hepatectomy was significantly increased with [(14)C]TdR uptake as a marker of DNA synthesis at 18 hours after surgery. On the other hand, the uptake was not accelerated by CCl(4)-administration, though it significantly increased [(14)C]TdR uptake. There were no differences of [(11)C]choline uptake acceleration following partial hepatectomy among the three parts of the regenerating liver. [(18)F]FDG uptake was accelerated in the regenerating liver on either partial hepatectomy or CCl(4)-administration. The magnitude of the increase in [(18)F]FDG uptake in the regenerating liver induced by partial hepatectomy was greater than that for [(11)C]choline. [(11)C]Choline uptake in the liver was accelerated by partial hepatectomy, but not by CCl(4)-administration. This might be expected given that the differentiation between proliferating tissues such as tumor and inflammatory tissue was possible by [(11)C]choline-PET.
Animals↗
A high-fat diet impairs liver regeneration in C57BL/6 mice through overexpression of the NF-kappaB inhibitor, IkappaBalpha.
Despite the growing incidence of obesity, knowledge of how this condition, as well as associated steatosis, affects liver regeneration remains scarce. Many previous studies have used models of steatohepatitis or obesity induced by genetic alterations. In contrast, our studies on liver regeneration have focused on the effects of obesity resulting solely from high amounts of fat in the diet. This model more closely reflects the detrimental effects of dietary habits responsible for increased morbidity due to obesity and its complications in well-developed Western societies. Impairment of liver regeneration was observed after partial hepatectomy in mice fed a high-fat diet. Fatty livers were more susceptible to posthepatectomy damage and failure. The underlying molecular mechanism was associated with increased inhibitor of nuclear factor-kappa B alpha (IkappaBalpha) expression, which inhibited nuclear factor-kappa B (NF-kappaB) activation and induction of its target genes, cyclin D1 and Bcl-xL, increasing sensitivity to apoptosis initiated by elevated tumor necrosis factor-alpha. In addition, since mice fed with a high-fat diet have higher leptin levels caused by increased adiposity, our work supports the hypothesis that the impairment of regeneration previously seen in genetically obese mice indeed results from liver steatosis rather than the disruption of leptin signaling. In conclusion, high fat in the diet impairs liver regeneration and predisposes steatotic livers to increased injury through IkappaBalpha overexpression and subsequent NF-kappaB inhibition.
Animals↗
The effect of amrinone on liver regeneration in experimental hepatic resection model.
BACKGROUND: The phosphodiesterase inhibitors (PDEIs) have been proposed to improve hepatic reperfusion injury and hepatosplanchnic circulation, but the effects of these agents on liver regeneration have not been investigated thoroughly. The aim of this study was to investigate the effect of amrinone, a PDEI, on liver regeneration in rats. MATERIALS AND METHODS: Sixty rats were divided into two groups, control and amrinone. Each group was then divided into three groups (n=10). An infusion of amrinone to the study group and of 0.9% NaCl to the control group was performed. Seventy percent liver resection was performed to the rats during the first hour of infusion. The infusion was maintained for 17 h after resection. A total of 18 h infusion was performed. Rats were allowed to survive for 24, 48, and 72 h, and then they were sacrificed. Biochemical, morphological, hematological, and histopathologic measurements and assessments were performed. RESULTS: There were statistically significant differences between the amrinone and control groups in alkaline phosphatase and relative liver weights at 24, 48, and 72 h (P<0.05). There also were statistically significant differences between the groups in AST, bilirubin, and albumine levels at 24 h, ALT and prothrombine time levels at 48 h, and aspartate aminotransferase and alanine aminotransferase levels at 72 h (P<0.05). Hepatic ATP levels, mitotic index, and proliferating cell nuclear antigen labeling index were significantly higher in amrinone group compared with control group at all three time intervals (P<0.05). CONCLUSIONS: Amrinone improves both morphological and functional liver regeneration after liver resection.
Alanine Transaminase↗
The effects of hyperbaric oxygen treatment on oxidant and antioxidants levels during liver regeneration in rats.
The effects of hyperbaric oxygen (HBO) therapy on oxidant/antioxidant metabolism are controversial and its effects on hepatic regeneration are not known. In this study, we investigated a possible beneficial effect of HBO therapy on oxidant and antioxidants levels during liver regeneration. To conduct this study, seventy percent hepatectomy was performed on forty-eight Spraggue-Dawley rats and the rats were divided into two equal groups: HBO-treated group and untreated group (non-HBO group). We determined the levels of malondialdehyde (MDA), an oxidative stress marker, and the levels of antioxidant enzymes/reagents, including glutathione (GSH), superoxide dismutase (SOD) activity, copper (Cu) and zinc (Zn), in the remnant liver samples. We also measured mitotic index (MI) and proliferating cell nuclear antigen (PCNA) levels to assess the degree of liver regeneration. HBO treatment significantly decreased MDA levels, whereas it increased SOD activity, GSH and Zn levels. In contrast, Cu levels were lower in the HBO-treated livers than the levels in the untreated remnant livers. The effect of HBO treatment may be mediated by the suppression of certain enzymes that are responsible for lipid peroxidation. In addition, HBO treatment may induce the production of antioxidant enzymes/reagents by remnant liver tissues. The HBO-treated rats maintained their body weights but the untreated rats lost body weights. HBO treatment also increased MI and PCNA levels, indicating HBO treatment enhances liver regeneration. These results indicate that HBO treatment has beneficial effects on liver regeneration by decreasing MDA and by increasing antioxidant activities. We therefore suggest that HBO therapy may be useful after liver resection.
Animals↗
Influence of buthionine sulfoximine, S-adenosylmethionine and glutathione on liver regeneration following partial hepatectomy.
This study was designed to evaluate the effect of derangement in methionine metabolism, and the effects of S-adenosylmethionine (SAM) and glutathione (GSH) on liver regeneration. Rats were treated immediately and 6 h after 70% hepatectomy (PH) as follows: (1) SAM, (2) GSH, (3) buthionine sulfoximine (BSO; inhibitor of SAM and GSH synthesis), (4) BSO + SAM, (5) BSO + GSH, and (6) buffer solution (B). The control group consisted of laparotomized animals treated with B. The increase in hepatic DNA synthesis, hepatocyte mitotic activity, and protein synthesis were observed in PH rats while in BSO rats, a delayed onset of liver regeneration was observed. SAM induced an earlier onset of hepatocyte mitotic activity, and reduced the inhibitory effect of BSO. GSH treatment exerted an inhibitory effect on liver regeneration and worsened the negative effect of BSO. It is concluded that derangement in methionine metabolism can impair the development of liver regeneration. The data also demonstrate the favourable effect of SAM and negative effect of GSH.
Amino Acids↗
The role of putrescine in modulation of DNA synthesis in regenerating liver of rats pretreated with 5-azacytidine.
The relationship between polyamine metabolism and DNA synthesis in regenerating liver was investigated using normal and 5-azacytidine-treated rats. The increase of DNA synthesis in regenerating rat liver was completely inhibited by administration of the analogue 1 h after partial hepatectomy. On the contrary, early and enhanced increase (modulation) of DNA synthesis was observed when the analogue was injected 24 h before partial hepatectomy. Changes in ornithine decarboxylase [EC 4.1.1.17] activity and the tissue levels of polyamines in liver remnants showed similar patterns in normal and 5-azacytidine-pretreated rats, except that the putrescine level in removed liver and the spermidine level in the S-phase were significantly higher in the drug-pretreated rats. On the other hand, a single injection of the analogue into intact rats evoked marked increase in hepatic ornithine decarboxylase activity followed by increase in the tissue level of putrescine, but not of spermidine or spermine. No similar increase in the enzyme activity was detected after injection of 5-aza-2'-deoxycytidine, which did not cause modulation of DNA synthesis. No modulation of DNA synthesis in regenerating liver of rats pretreated with 5-azacytidine was observed when partial hepatectomy was carried out before increase of the hepatic level of putrescine. In addition, a positive and highly significant correlation was observed between the level of putrescine in the liver removed at partial hepatectomy and the extent of modulation of DNA synthesis in regenerating liver of rats pretreated with 5-azacytidine. These results suggest that putrescine plays an important role in modulation of DNA synthesis and support our previous proposal that putrescine may have at least two roles in DNA synthesis.
Animals↗
Early pregnancy factor in liver regeneration after partial hepatectomy in rats: relationship with chaperonin 10.
Early pregnancy factor is not only a product of dividing embryonic and neoplastic cells, as demonstrated previously, but also of normal proliferating cells. Eight hours after partial hepatectomy in rats, early pregnancy factor was detected in serum. It rose to a peak by 48 hr. Neutralization of early pregnancy factor in vivo by passive immunization with specific antibodies, 18 hr after partial hepatectomy, resulted in a significant decrease in the uptake of [3H]thymidine by the liver remnant, measured 4 to 6 hr later. These results suggest that during liver regeneration, early pregnancy factor is essential to the sequence of events that culminates in DNA synthesis and cell division. Recently we purified early pregnancy factor from human platelets and determined by mass spectrometry a precise molecular mass of 10,843 Da. Amino acid sequencing (approximately 72% of the molecule) demonstrated that early pregnancy factor is highly homologous with chaperonin 10, a stress-inducible mitochondrial protein, and that platelet-derived early pregnancy factor and rat chaperonin 10 share similar biochemical and immunological properties. In this study we show that early pregnancy factor, purified from regenerating rat liver and from serum taken 24 hr after hepatectomy, shares these properties. In addition, antibodies to early pregnancy factor, effective in passive immunization studies, recognize chaperonin 10, whereas chaperonin 10 antibodies bind to early pregnancy factor from regenerating liver and posthepatectomy serum. We propose that early pregnancy factor/chaperonin 10 is selectively released from proliferating cells and, in an autocrine or paracrine mode (or both) is involved in DNA synthesis.
Adsorption↗