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PubMed2003

Postoperative liver regeneration and complication in live liver donor after partial hepatectomy for living donor liver transplantation.

The safety of donor is the first priority during whole procedure in living donor liver transplantation. We evaluated the short-term results of partial living donor liver transplantation in the view of donor safety. We prospectively evaluated the extent of liver regeneration, the recovery of liver function, and the perioperative complications in 41 live liver donors for partial liver transplantation at our institution. We developed novel personal computer volumetry program for the evaluation of liver regeneration. Serial CAT scan was performed preoperatively, at postoperative day (POD) #7 and POD #30 and liver volume was measure by using volumetry program. The serum level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (T.bil.) was serially monitored. There were 34 males and 7 females. The mean preoperative liver volume was 1320.6 cm3. The remained mean liver volume was 687.8 cm3 after harvest, and increased to 954.4 cm3 (144.6%) at POD #7, and 1169.5 cm3 (81.4%) at POD #30, which was 88.5% of preoperative total liver volume. The serum level of ALT/ AST and T.bil. peaked at POD #1 and declined thereafter, and finally returned to preoperative level at POD #30. The regeneration rate was significantly different by age, type and size of graft according to the donors. Six donors experienced postoperative complications and they were four pleural effusions, one wound infection and one case of bile duct stenosis that was treated by endoscopic nasal biliary drainage. All of them were right lobe donors. In conclusion, the donor liver regenerated up to 88.5% of preoperative volume with full recovery of liver function at POD #30. Right lobe donors suffered more complications and need more meticulous operative and postoperative care than left lobe or left lateral segment donors.

Adolescent↗
PubMed1976

Changes in transcription of endogenous type-C virus genome during mouse liver regeneration.

In the present study the extent of endogenous, type-C virus genome transcription in normal and regenerating mouse liver was analysed by using the technique of nucleic acid hybridization. The RNA preparations from regenerating liver tissues collected at various intervals following partial hepatectomy, and from normal liver samples of BALB/c mice, were hybridized to 3H-DNA complementary to 60 to 70S RNA of an endogenous, N-tropic virus, released spontaneously from BALB/c mouse cells in culture. Although partial transcription of the endogenous virus genome can be clearly detected in normal liver, a significant increase in the level of virus-specific RNA synthesis in the regenerating liver, in comparison to normal liver, is apparent, following partial hepatectomy. This increase in virus-specific RNA synthesis attains its highest level just before the level of DNA synthesis in the regenerating liver reaches its maximum. These observations may indicate a qualitative or quantitative change in the endogenous type-C virus genome transcription pattern in hepatocytes, in response to partial hepatectomy and suggest that this change in the transcription pattern and the initiation of cell proliferation, in regenerating livers, are probably sequential and related events.

Animals↗
PubMed1986

[Liver regeneration and the immune system. III. Suppressor activity of splenic adherent cells activated in vivo by liver regeneration].

It has been shown in the previous reports the immune system of mice is activated during liver regeneration following partial hepatectomy and lymph node cells activated in vivo suppress the syngeneic mixed hepatectomized liver cell-lymphocyte reaction (sMLHLR). In this report, it is demonstrated that the suppressor activity of lymphocytes in vivo by liver regeneration exists in lymph node T cells and splenic adherent cells, but not in lymph node B cells. This suppressive activity of splenic adherent cells is blocked with indomethacin or aspirin. Each of these compounds in nontoxic doses inhibited macrophage-mediated suppression suggesting that the release of prostaglandins by macrophages played an essential role in inhibiting the sMLHLR.

Animals↗
PubMed2002

[Cloning differentially expressed genes by suppression subtractive hybridization in rat liver regeneration].

The cDNA from rat regenerating liver tissue was used as the tester and that from normal liver was used as the driver. A highly efficient subtractive cDNA library was constructed by suppression subtractive hybridization(SSH). After screening, 31 clones from 50 clones which were derived from the cDNA library were inserted by 60-400 bp cDNA fragments. 24 cDNA fragments corresponded to known genes and 7 cDNA fragments were unknown sequences (GenBank accession number: BG447490-447496).

English Abstract↗
PubMed2001

Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration.

The liver responds to multiple types of injury with an extraordinarily well orchestrated and tightly regulated form of regeneration. The response to partial hepatectomy has been used as a model system to elucidate the molecular basis of this regenerative response. In this study, we used cyclooxygenase (COX)-selective antagonists and -null mice to determine the role of prostaglandin signaling in the response of liver to partial hepatectomy. The results show that liver regeneration is markedly impaired when both COX-1 and COX-2 are inhibited by indocin or by a combination of the COX-1 selective antagonist, SC-560, and the COX-2 selective antagonist, SC-236. Inhibition of COX-2 alone partially inhibits regeneration whereas inhibition of COX-1 alone tends to delay regeneration. Neither the rise in IL-6 nor the activation of signal transducer and activator of transcription-3 (STAT3) that is seen during liver regeneration is inhibited by indocin or the selective COX antagonists. In contrast, indocin treatment prevents the activation of CREB by phosphorylation that occurs during hepatic regeneration. These data indicate that prostaglandin signaling is required during liver regeneration, that COX-2 plays a particularly important role but COX-1 is also involved, and implicate the activation of CREB rather than STAT3 as the mediator of prostaglandin signaling during liver regeneration.

6-Ketoprostaglandin F1 alpha↗
PubMed2005

Liver regeneration after split liver transplantation.

BACKGROUND: The number of split liver transplantations (SLT) has increased in the last 5 years. Regeneration after the loss of hepatic tissue is a fundamental response to liver injury. Because partial-liver grafts may not be an optimal size for recipients,the purpose of this study was to investigate the regeneration of graft liver after SLT. METHODS: Four recipients have undergone SLT at our hospital since 2002. The graft liver volume (GLV) in the postoperative day (POD) was measured by computed tomography (CT) and the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB), prealbumin (PA) and albumin (ALB) were monitored. The GLV at different postoperative times was compared to the recipient's standard liver volume (SLV) and the liver volume regeneration ratio (LVRR) was calculated. In order to compare SLV in recipient 2, we measured the total liver volume including the graft and the residual native liver as the GLV. RESULTS: The GLV/SLV at POD120 and POD360 of recipient 1 was measured 114% (1159.32 cm(3)/1016.95 cm(3)), 97% (986.44 cm(3)/1016.95 cm(3)) with the LVRR being -11.0%, -24.3%, respectively. For recipient 2, it was measured 96% (927.32 cm(3)/965.96 cm(3)) and 100% (968.98 cm(3)/965.96 cm(3)), with the LVRR being 24.4%, 30.0%, respectively. The initial graft volume of segment II, III was 265.36 cm(3) and increased to 335.24 cm(3) and 360.56 cm(3) at POD120 and POD360, respectively, with the LVRR being 26.3% and 35.9%, respectively. The GLV/SLV at POD60 of recipient 3 was 86% (893.04 cm(3)/1038.42 cm(3)) and the LVRR was 12.0%. For recipient 4, it was 90% (567.48 cm(3)/630.54 cm(3)) whereas the LVRR was 20.0%. The serum levels of ALT, AST and TB in all recipients declined gradually and returned to normal while the serum levels of PA and ALB increased to normal. The serum levels of ALT and AST peaked within 3 days after SLT. The neurological symptoms of Wilson's disease in recipient 2 were improved markedly. The levels of serum copper and copper-protein decreased to 30 mg/L, 120 mg/L at POD120 and the Kayser-Fleischer rings began to obliterate. CONCLUSIONS: The size of the transplanted liver after SLT tends to converge to the standard liver volume with time and it is adequate clinically for SLT to meet the need of the body's metabolic demands. The functional recovery of the graft liver occurs earlier than the morphological restoration.

Adult↗
PubMed1988

A study of liver regeneration using fetal rat liver tissue transplanted into the spleen.

The liver morphology of fetal hepatic tissue transplanted into an ectopic location was investigated over one year period. Fetal liver fragments prepared from a maternal rat on the 18th or 19th day of pregnancy were injected into the splenic parenchyma of syngeneic rats using a 21 gauge needle. Histologically, the fetal liver did not essentially show any apparent lobular architecture or cord structure. The transplanted fetal hepatic tissues survived and formed hepatic cords in the spleen instead of undergoing degeneration and necrosis. Three characteristic features became complete during the 4 weeks following transplantation, namely; clumps of hepatocytes with obvious hepatic cords and sinusoids, markedly proliferating bile ducts and proliferating individual hepatocytes. Macroscopic nodules of the hepatocytes on the spleen were seen at about 6 months after transplantation. When the differentiation of the transplanted fetal hepatic tissue was compared with the development of a normal neonatal liver after birth, it was delayed by only about one week, while there was no proliferation of bile ducts in the normal neonatal liver. This experimental model provides a useful system for investigating liver regeneration and the mechanism of cell growth.

Animals↗
PubMed2004

Liver-enriched transcription factors in liver function and development. Part II: the C/EBPs and D site-binding protein in cell cycle control, carcinogenesis, circadian gene regulation, liver regeneration, apoptosis, and liver-specific gene regulation.

In the first part of our review (see Pharmacol Rev 2002;54:129-158), we discussed the basic principles of gene transcription and the complex interactions within the network of hepatocyte nuclear factors, coactivators, ligands, and corepressors in targeted liver-specific gene expression. Now we summarize the role of basic region/leucine zipper protein family members and particularly the albumin D site-binding protein (DBP) and the CAAT/enhancer-binding proteins (C/EBPs) for their importance in liver-specific gene expression and their role in liver function and development. Specifically, regulatory networks and molecular interactions were examined in detail, and the experimental findings summarized in this review point to pivotal roles of DBP and C/EBPs in cell cycle control, carcinogenesis, circadian gene regulation, liver regeneration, apoptosis, and liver-specific gene regulation. These regulatory proteins are therefore of great importance in liver physiology, liver disease, and liver development. Furthermore, interpretation of the vast data generated by novel genomic platform technologies requires a thorough understanding of regulatory networks and particularly the hierarchies that govern transcription and translation of proteins as well as intracellular protein modifications. Thus, this review aims to stimulate discussions on directions of future research and particularly the identification of molecular targets for pharmacological intervention of liver disease.

Animals↗
PubMed2003

Liver regeneration in a retrorsine/CCl4-induced acute liver failure model: do bone marrow-derived cells contribute?

BACKGROUND/AIMS: Adult bone marrow contains progenitors capable of generating hepatocytes. Here a new liver failure model is introduced to assess whether bone marrow-derived progeny contribute to liver regeneration after acute hepatotoxic liver failure. METHODS: Retrorsine was used to inhibit endogenous hepatocyte proliferation, before inducing acute liver failure by carbon tetrachloride. Bone marrow chimeras were generated before inducing liver failure to trace bone marrow-derived cells. Therefore, CD45 and major histocompatibility complex (MHC) class I dimorphic rat models were applied. RESULTS: Early after acute liver failure a multilineage inflammatory infiltrate was observed, mainly consisting of granulocytes. In long-term experiments small numbers of CD90+/CD45- cells of donor origin occurred in clusters associated with portal triads. Bone marrow cell infusion was not able to enhance liver regeneration. Cellular hypertrophy was the predominant way of liver mass regeneration in models applying retrorsine. CONCLUSIONS: Retrorsine pretreatment did not affect sensitivity for carbon tetrachloride. A multilineage inflammatory infiltrate was observed in rats whether pretreated with retrorsine or not. Few donor cells co-expressing CD90 (THY 1) were present in recipient livers, which may resemble donor-derived hematopoietic progenitors or oval cells. No other donor cells within liver parenchyma were detected. This is in contrast to other cell infusion models of acute cell death.

Animals↗
PubMed1995

Mitochondrial oxidative phosphorylation and intracellular glutathione compartmentation during rat liver regeneration.

The rate of mitochondrial oxidative phosphorylation and the cytosolic and mitochondrial total and oxidized glutathione concentrations were studied in regenerating rat livers after partial (70%) hepatectomy. The rate of mitochondrial oxidative phosphorylation progressively decreased during the early prereplicative phase of liver regeneration. This was accompanied by a progressive decrease in mitochondrial, but not cytosolic, glutathione concentration. Twenty-four hours after partial hepatectomy, both the rate of adenosine triphosphate (ATP) synthesis and the amount of mitochondrial glutathione were depressed by 50% with respect to controls (sham-operated animals). During the second replicative phase, both the oxidative phosphorylation rate and mitochondrial glutathione concentration were recovered; however, the kinetics of the recovery were different, being the total amount of mitochondrial glutathione completely restored 48 hours after partial hepatectomy, whereas 72 hours were needed for the recovery of oxidative phosphorylation. The decrease in the rate of oxidative phosphorylation, during the early phase of liver regeneration, appeared to be secondary to the decreased content of the catalytic subunit beta-F1 of the ATP synthase complex, which in turn was shown to be linearly related to the decrease of intramitochondrial glutathione. These observations suggest that the two phenomena may be due to the previously reported increased free radical production during the early phase of liver regeneration. The depression of mitochondrial glutathione after partial hepatectomy may play a contributory role in structural and functional alterations of mitochondria occurring in the first retrodifferential phase of liver regeneration.

Adenosine Triphosphate↗
PubMed1998

Regulation of G1 cyclin-dependent kinases in liver regeneration.

The liver serves as a suitable model for studying tissue regeneration. Although various growth factors have been implicated in the promotion of this process, their precise role in liver regeneration remains to be elucidated. Whatever the extracellular signals may be, they all converge on cell cycle regulators in the nucleus, where the sequential activation of cyclin-dependent kinases (Cdk) takes place. The activities of Cdk are regulated positively through their association with cognate cyclins, and negatively via interactions with Cdk inhibitors. In this review article, our recent data as well as results of previous reports on how these cell cycle regulators trigger and/or terminate the process of liver regeneration are summarized. The authors believe that 'knockout' mice, in which specific genes are deleted, will be useful for providing further insight into the positive and negative regulation of liver regeneration.

Animals↗
PubMed1999

Effect of ethanol on tumor necrosis factor signaling during liver regeneration.

OBJECTIVES: The liver has tremendous regenerative capacity but can be damaged by toxins, such as ethanol (EtOH). It has long been known that EtOH inhibits liver regeneration. Recent work demonstrates that the proinflammatory cytokine, tumor necrosis factor ( (TNF), is required for normal liver regeneration, as well as for EtOH-related liver damage. Therefore, it is conceivable that EtOH promotes liver damage by altering TNF signal transduction in such a way that proliferative signals are aborted and death signals predominate. DESIGN AND METHODS: Anti-TNF antibodies were used to characterize the TNF signals that are induced in the regenerating liver after two-thirds (partial) hepatectomy (PH) in normal mice and rats. Then, these TNF-regulated processes were evaluated in animals that had been fed nutritionally replete, EtOH-containing diets for several weeks before PH. RESULTS: During normal liver regeneration, TNF induces potentially dangerous responses, such as increased mitochondrial ROS production, but also promotes the activation of several factors, including NF kappa B, Jun N-terminal Kinase (JNK), and various mitochondrial membrane proteins, which are likely to permit hepatocytes to survive apoptotic and oxidant stress. Previous EtOH exposure inhibits the normal regenerative induction of NF kappa B and JNK. CONCLUSIONS: These finding are consistent with the possibility that potential hepatotoxins compromise the balanced induction of toxic and trophic signals by TNF.

Animals↗
PubMed2003

Hypothalamic vasopressin release and hepatocyte Ca2+ signaling during liver regeneration: an interplay stimulating liver growth and bile flow.

Liver regeneration after partial hepatectomy is a plastic process during which the mechanisms that coordinate liver mass restoration compensate one another through a complex regulatory network of cytokines, growth factors, and hormones. Vasopressin, an agonist that triggers highly organized Ca2+ signals in the liver, may be one of these factors, although little in vivo evidence is available in support of this hypothesis. We provide evidence that hypothalamic vasopressin secretion is stimulated early after partial hepatectomy. Although hepatocytes were fully responsive to vasopressin during the first hours of regeneration, they became desensitized and exhibited slow oscillating Ca2+ responses to vasopressin on the following days. On the first day, hepatocyte V1a receptor density decreased and its lobular gradient increased in hepatectomized rats. By antagonizing the V1a receptor in vivo, we demonstrated that vasopressin contributes to NF-kappaB and cyclin (D1 and A) activation, to hepatocyte progression in the cell cycle, and to liver mass restoration. Finally, vasopressin exerted a choleretic effect shortly after hepatectomy, both in the isolated perfused liver and in the intact rat. In conclusion, we provide compelling in vivo evidence that vasopressin contributes significantly to growth initiation and bile flow stimulation in the early stages of liver regeneration.

Animals↗
PubMed1999

Nutritional modulation of liver regeneration by carbohydrates, lipids, and amino acids: a review.

The survival of patients after a life-threatening hepatic injury of varying etiology depends on the ability of the remaining hepatocytes to regenerate. Thus, the stimulation of hepatic regeneration can have tremendous therapeutic relevance. Experimental studies--performed mostly on a model of regenerating rat liver after partial hepatectomy--indicate that glucose administration inhibits, whereas infusion of a lipid emulsion can enhance, the rate of liver regeneration. However, the inhibitory effect of glucose on liver regeneration is not observed when glucose is administered together with other nutrients. The results further indicate that administration of a standard amino acid mixture without energy substrate has an inhibitory effect and that development of liver regeneration can be favorably influenced by branched-chain amino acids (valine, leucine, and isoleucine) and glutamine.

Amino Acids↗
PubMed2006

Disruption of phospholipase Cdelta4 gene modulates the liver regeneration in cooperation with nuclear protein kinase C.

Phospholipase Cdelta4 (PLC delta4) gene has been cloned from the cDNA library of regenerating rat liver. Using PLC delta4 gene-disrupted mice (PLC delta4(-/-)), we studied a role of PLC delta4 during liver regeneration after partial hepatectomy (PH). In PLC delta4(-/-), liver regeneration occurred in an apparently normal way. However, BrdU-indices indicated that PLC delta4 gene disruption delayed the onset of DNA synthesis by 2 h. Noticeably, the BrdU-indices in PLC delta4(+/+) remained rather constant throughout S phase, 25-35%, whereas in PLC delta4(-/-), it fluctuated drastically from 25% at 34 h to 65% at late S, 42 h after PH. This fact showed that PLC delta4 gene disruption caused a higher synchronization of cell proliferation. The mRNA for PLC delta4 in PLC delta4(+/+) appeared at late G1, and the expression continued throughout S phase. PLC activity increased transiently in chromatin at the late G1 and S phases in only PLC delta4(+/+), but not in PLC delta4(-/-). The specific increases in PLC activity well correlated with the transient increases of protein kinase C (PKC) alpha in chromatin of PLC delta4(+/+). PKC epsilon also increased transiently in chromatin from PLC delta4(+/+) at late S. It is concluded that PLC delta4 regulates the liver regeneration in cooperation with nuclear PKC alpha and epsilon.

Animals↗
PubMed2002

lal-1: a differentially expressed novel gene during proliferation in liver regeneration and in hepatoma cells.

BACKGROUND: During liver regeneration, 95% of the resting hepatocytes enter in G1/S phase of the cell cycle. A number of hormones, growth factors and cytokines were identified that activate signal transduction pathways playing a primary role in hepatocyte proliferation. A wide and representative cDNA library containing 1.5 x 106 independent clones was constructed from regenerating liver in order to identify and characterize gene the products which play a crucial role in the first hours of the proliferative process of liver regeneration. RESULTS: A novel gene expressed in liver regeneration was cloned by subtractive hybridization. The putative protein displays in the N'-terminal a annexin-like domain and an aminopeptidase domain. We named the novel gene Liver Annexin Like-1 (lal-1). The lal-1 gene is modulated during liver regeneration, in hepatoma cells following physiological stimulation and after cAMP induction. CONCLUSION: The results indicate that lal-1 is involved in liver regeneration and that its expression is finely regulated during proliferative process. The isolation of lal-1 paves the way for a further characterization helping to assess lal-1 involvement in cell function and proliferation.

Animals↗
PubMed2005

Contribution of the lymphotoxin beta receptor to liver regeneration.

The liver has an enormous capacity to regenerate in response to insults, but the cellular events and molecules involved in liver regeneration are not well defined. In this study, we report that ligands expressed on the surface of lymphocytes have a substantial effect on liver homeostasis. We demonstrate that a T cell-restricted ligand, homologous to lymphotoxin, exhibits inducible expression, competes with herpesvirus glycoprotein D for herpesvirus entry mediator on T cells (LIGHT), signaling through the lymphotoxin receptor (LTbetaR) expressed on mature hepatocytes induces massive hepatomegaly. Using genetic targeting and a receptor fusion protein, we further show that mice deficient in LTbetaR signaling have a severe defect in their ability to survive partial hepatectomy with marked liver damage and failure to initiate DNA synthesis after partial hepatectomy. We further show that mice deficient in a LTbetaR ligand, LTalpha, also show decreased ability to survive partial hepatectomy with similar levels of liver damage and decreased DNA synthesis. Therefore, our study has revealed an unexpected role of lymphocyte-restricted ligands and defined a new pathway in supporting liver regeneration.

Animals↗