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PubMed1980

The proliferation activity of the rat thymocytes after partial hepatectomy.

The influence of partial hepatectomy, unilateral nephrectomy and shamoperation on thymocyte proliferation capacity in male rats was investigated. The wet weight and the cell number declines significantly after partial hepatectomy. A stimulation of mitotic activity and H3TdR incorporation on day 3 to day 6 was also observed in partially hepatectomized animals. The polyamine content of the thymocytes was transiently decreased 2 days post partial hepatectomy and shamoperation. Thereafter the amine concentrations increased and remained elevated in the case of partially hedatectomized animals. No significant changes in the content of histamine were observed.

Animals↗

PubMed1998

Pattern of methionine adenosyltransferase isoenzyme expression during rat liver regeneration after partial hepatectomy.

The present report investigates the pattern of expression of liver-specific and extrahepatic methionine adenosyltransferase (MAT) isoenzymes in regenerating rat liver after partial hepatectomy. The results show that there is a switch in the expression of these isoenzymes that is coincident with maximal cell proliferation in the remaining liver lobes. Extrahepatic MAT levels increase about three times 4 h after hepatectomy, reaching a maximum 36 h later. This is accompanied by a rapid and transient increase in total MAT activity and levels of related metabolites S-adenosyl-L-methionine and S-adenosyl-L-homocysteine. Liver-specific MAT levels are reversibly down-regulated within 24-48 h post surgery. Our results indicate that MAT isoenzyme expression is tightly regulated during liver regeneration after two-third hepatectomy. The implications of these observations for evaluation of the degree of liver regeneration are briefly discussed.

Animals↗

PubMed2000

Extended left hepatectomy (left hepatic trisegmentectomy) in childhood.

BACKGROUND/PURPOSE: Extended left hepatectomy, also referred to as left hepatic trisegmentectomy, in which segments II, III, IV, V, and VIII are excised, is rarely performed in children. Experience with 7 such resections is reported to describe the anatomy, technique, indications, and outcomes of the operation. METHODS: The medical records of all pediatric patients treated at our institution over the last 15 years who underwent extended left hepatectomy were reviewed. Demographic information as well as operative, pathological, and follow-up data were analyzed. RESULTS: Seven patients underwent extended left hepatectomy over this period. There were 5 boys and 2 girls ranging in age between 4 months and 9 years with a median age of 3.1 years. Follow-up ranged from 8 months to 5 years with a median of 3.5 years. Diagnoses included hepatoblastoma (HB, n = 3), focal nodular hyperplasia (FNH, n = 1), leiomyosarcoma (LMS, n = 1), hepatocellularcarcinoma (HCC, n = 1), and metastatic neuroblastoma (NB, n = 1). All surgical margins were grossly negative. Median operative blood loss was 13 mL/kg (range, 5 to 32 mL/kg), and mean hospital stay was 9 days (range, 7 to 12 days). No major intra- or postoperative complications were encountered, and there was no perioperative mortality. The 3 HB patients, 1 FNH patient, 1 LMS patient, and 1 NB patient are without evidence of disease, whereas the 1 child with HCC died of recurrent and distant disease. The 6 surviving children have normal hepatic function. CONCLUSION: Although technically challenging and rarely performed, extended resection of the left hepatic lobe is feasible in children and can yield curative results with minimal morbidity.

Carcinoma, Hepatocellular↗

PubMed2002

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↗

PubMed1998

Immediate onset of DNA synthesis in remnant rat liver after 90% hepatectomy by an administration of follistatin.

BACKGROUND/AIM: Follistatin is an antagonist of activins and is effective in promoting liver regeneration after 70% hepatectomy. To examine its efficacy under more critical conditions, we studied the effect of follistatin on liver regeneration in 90% hepatectomized rat. METHODS: Human recombinant follistatin was infused into the portal vein immediately after 90%, hepatectomy in 24-h-starved rats, and changes in the liver regeneration rate and nuclear bromodeoxyuridine labeling were measured. RESULTS: In control rats, nuclear labeling was first detected at 11 h of hepatectomy. In follistatin-treated rats, nuclear labeling was markedly increased at 3 h, and was significantly higher than that in control rats at 24, 72, 96, 120 and 144 h. The liver regeneration rate was significantly higher in follistatin-treated rats at 48, 72, 96, 120, 144 and 168 h. To determine the reason for the accelerated growth in starved rats, we compared the expression of mRNA for c-myc, p53, p21CIP1, p15INK4B, p27KIP1, and subunits of activins in fed and starved rats. mRNA for p21CIP1 and p15INK4B, but not p27KIP1 were decreased in 24 h-starved rats compared to the fed rats. mRNA for betaA subunit of activin was not detected in either fed or 24-h-starved rats, whereas that for betaC subunit was increased in starved rats. CONCLUSION: These results indicate that follistatin induces immediate onset of DNA synthesis in 90% hepatectomized rats and is quite effective in promoting liver regeneration.

Animals↗

PubMed1999

Effect of vascular endothelial growth factor on hepatic regenerative activity following partial hepatectomy in rats.

BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF) is an angiogenic factor with a growth-promoting effect that is thought to be restricted to vascular endothelial cells. Its essential role during liver regeneration has yet to be determined. The aim of this study was to document the effect of exogenous VEGF administration on liver regeneration in rats undergoing submaximal hepatic resections. METHODS: Adult male Sprague-Dawley rats (n = 4/group) undergoing 30% partial hepatectomy were administered 200 ng VEGF165 intravenously and were sacrificed at 24, 36, and 48 h postoperatively. Liver regeneration was monitored by measuring the restituted liver mass, proliferating cell nuclear antigen (PCNA) immunostaining, and hepatic PCNA protein by Western blot. RESULTS: Changes in restituted liver mass 48 h postsurgery were more prominent, but did not differ statistically between VEGF-treated and control rats (47% vs. 29%; p<0.06). Nevertheless, PCNA immunostaining showed increased labeling index of hepatocytes, apparent at 36 and 48 h after partial hepatectomy (38% vs. 18% [p<0.041 and 42% vs. 11% [p<0.021], respectively). Hepatic PCNA proteins measured by Western blot showed a 3-fold increase in VEGF-treated rats 48 h postsurgery compared with controls (p<0.01). CONCLUSION: Exogenous VEGF administration early after partial hepatectomy stimulates liver regeneration in rats. Whether or not VEGF165 is a direct mitogen for hepatocytes remains to be determined.

Animals↗

PubMed1983

Detection of the changes in protein distribution in rat serum after partial hepatectomy using two-dimensional electrophoresis under non-denaturing conditions.

The changes in rat serum protein distribution after partial hepatectomy were examined using two-dimensional electrophoresis, utilizing isoelectric focusing in polyacrylamide gel in the first dimension and pore gradient polyacrylamide gel electrophoresis in the second dimension. Drastic decreases in amount of protein were observed at more than twenty spot positions, and drastic increases in amount or newly appeared proteins were observed at eight spot positions. The amounts of albumin, immunoglobulin M and alpha 2-macroglobulin did not change relatively after hepatectomy. The time course of the changes was examined using a densitometer, and it was observed that almost all the serum proteins changed drastically at 24 h after hepatectomy.

Animals↗

PubMed1984

Detection of changes in rabbit serum proteins after partial hepatectomy by means of two-dimensional electrophoresis under non-denaturing conditions.

The changes in rabbit serum proteins after partial hepatectomy were examined by means of two-dimensional electrophoresis utilizing isoelectric focusing in a 4% polyacrylamide gel in the first dimension and a 4-30% pore gradient polyacrylamide gel in the second dimension. A rapid increase in seven proteins was observed after partial hepatectomy and a rapid decrease in two proteins. Major serum proteins, including albumin, immunoglobulin G, immunoglobulin M and alpha 2-macroglobulin, did not change. The time course of the changes was examined using a densitometer; the maxima of the changes were observed on day 3 after partial hepatectomy.

Animals↗

PubMedDate not supplied

Geranylgeranylacetone suppresses inflammatory responses and improves survival after massive hepatectomy in rats.

Overproduction of heat shock protein 70 (HSP70) in the liver protects hepatocytes under various pathologic conditions. In this study we examined the effects of a nontoxic HSP70 inducer, geranylgeranylacetone (GGA), on acute hepatic failure after 95% hepatectomy in rats. When GGA (100 mg/kg) or vehicle was intragastrically administered to rats 4 hours before 95% hepatectomy, all 25 rats pretreated with vehicle died within 60 hours after the operation, whereas 10 of 25 rats pretreated with GGA survived. During the 24-hour postoperative period, GGA significantly suppressed the release of aspartate or alanine aminotransferase and elevation of the serum interleukin-6 level, and completely inhibited an increase in the serum level of tumor necrosis factor-alpha. Histologic examinations showed that GGA prevented hemorrhagic necrosis, which was observed in vehicle-treated livers more than 12 hours after the operation. During the 24-hour postoperative period, HSP70 induction was absent in remnant livers of vehicle-treated rats. In contrast, GGA stimulated the HSP70 mRNA expression and HSP70 accumulation within 4 hours, and viable hepatocytes contained abundant HSP70 in their nuclei. Our results suggest that GGA may prevent acute liver failure after massive hepatectomy, at least in part, by enhancing HSP70 induction in the remnant liver.

Animals↗

PubMed2002

Acute-phase protein gene expression in rat liver following whole body X-irradiation or partial hepatectomy.

We studied the effect of total body X-irradiation and partial hepatectomy on the acute phase protein gene expression in rat liver. Male rats of AO strain were irradiated with high X-ray doses, without any visible tissue damage. In contrast, partial hepatectomy consisted of surgical removal of 40% liver tissue. The changes in liver mRNA concentrations for positive acute-phase reactants including cysteine protease inhibitor, alpha(1)-acid glycoprotein, fibrinogen and haptoglobin, and albumin as a negative reactant were monitored by Northern blot and slot-blot hybridizations using corresponding [32P]dCTP labeled cDNA probes. While in the first 24 h after the partial hepatectomy, liver mRNA levels for the positive acute-phase reactants increased, briefly followed by an immediate decrease, the duration and timing of the acute-phase responses to the whole body X-irradiation were slightly different and lasted for as long as 72 h. Although both treatments induced the mRNA expression of acute-phase reactants in rat liver, the observed variations in the duration and intensity of the changes in mRNA levels for the acute-phase proteins in these two types of tissue damage suggest the involvement of specific mechanisms in a fine tuning of the non-specific acute-phase responses to meet the unique requirements of the particular injury.

Acute-Phase Proteins↗

PubMed1996

Influence of partial hepatectomy on theophylline pharmacokinetics in rats.

The influence of partial hepatectomy on the pharmacokinetics of theophylline was determined in rats. The pharmacokinetics of intravenous theophylline was studied in unhepatectomized rats (control group: CG) and in hepatectomized rats (HG) 12 h after 70% hepatectomy. Liver function was monitored in both groups by measurements of total and direct bilirubin, transaminases GOT and GPT, and plasma protein. Seventy per cent hepatectomy caused significant liver dysfunction: transaminase levels (GOT and GPT) increased by 118 and 683%, respectively, and the total and direct bilirubin levels increased by 28.6 and 9.1%, respectively. At the same time, plasma concentrations of theophylline decreased significantly and half-life increased from 4.16 +/- 0.57 h (CG) to 7.08 +/- 0.69 h (HG), as did the distribution volumes values of central (Vc) and peripheral (Vp) compartments (Vc: CG, 0.18 +/- 0.03 L; HG, 0.24 +/- 0.03 L) (Vp: CG, 0.08 +/- 0.05 L; HG, 0.13 +/- 0.05 L). The percentage of theophylline binding to plasma proteins decreased from 44.3% in CG to 33.8% in HG. The theophylline intrinsic clearance (CLint) dropped from 1.35 +/- 0.43 mL/min (CG) to 0.93 +/- 0.10 mL/min (HG)1, which can be attributed to a significant fall in the quantity of hepatic microsomal enzymes. These modifications on the pharmacokinetics of drugs with low hepatic extraction coefficients, such as theophylline, should be considered when dosage regimens during the posthepatectomy hepatic regeneration period are planned.

Animals↗

PubMed2002

Analysis of donor risk in living-donor hepatectomy: the impact of resection type on clinical outcome.

The progressive shortage of liver donors has mandated investigation of living-donor transplantation (LDT). Concerns about increasing risk to the donor are evident, but the impact of the degree of parenchymal loss has not been quantified. We analyzed clinical and biological variables in 45 LDT performed by our team over 2years to assess risks faced in adult LDT. All donors are alive and well with complete follow-up through to February 2001. When the three operations were compared, right hepatectomy (RH) was significantly longer in terms of anesthesia time and blood loss compared with left hepatectomy (LH) and left lobectomy (LL). Donor remnant liver was significantly reduced after RH compared with LH and LL. There were significant functional differences as a consequence of the remnant size, measured by an increase in peak prothrombin time after RH. RH for adults represents a markedly different insult from pediatric donations in terms of parenchymal loss and early functional impairment. Left hepatectomy donation offers modest advantage over right lobes but seems to confer substantial technical risk for a small gain in graft size. Unless novel strategies are developed to enhance liver function of the LH graft in the adult recipient, right lobe donation will be necessary for adult LDT.

Adult↗

PubMed1978

Repeated partial hepatectomy as a promoting stimulus for carcinogenic response of liver to nitrosamines in rats.

Partial hepatectomy 24 h before a single i.p. dose of dimethylnitrosamine, diethylnitrosamine or ethylmethylnitrosamine increased the carcinogenic response in the liver of rats as determined by the number of tumours and the number of "focal proliferations" produced. Secondly, in rats given a single i.p. dose of diethylnitrosamine, 3 partial hepatectomies 5, 10 and 15 weeks after dosing the animals increased the carcinogenic response in the liver. The stimulus of repeated partial hepatectomy therefore appears to act as a "promoting agent" for liver carcinogenesis, that is if the single dose of diethylnitrosamine is regarded as an "initiating agent" in the terms of the two-stage hypothesis.

Animals↗

PubMed1983

Promotion mechanism of phenobarbital and partial hepatectomy in DENA hepatocarcinogenesis cell kinetics effect.

Diethylnitrosamine (DENA, 10 mg kg-1 per day) was fed to rats for 2, 4 and 6 weeks. One week after the cessation of DENA, animals were submitted either to partial hepatectomy or to phenobarbital administration. Partial hepatectomy did not promote neoplastic transformation, except after a 6-week DENA treatment. A minimum of phenobarbital was required to reach a significant promoting effect in DENA carcinogenesis. A too-limited treatment was ineffectual but could be compensated for by prolonged DENA administration. The phenobarbital treatment became unnecessary when neoplastic nodules were present. Phenobarbital continuously given after the carcinogen administration promoted neoplastic transformation even after a subcarcinogenic DENA treatment (2 weeks). It accelerated the pathological evolution and increased the tumour incidence. In these conditions, phenobarbital increased the proliferation advantage of preneoplastic cells over normal cells. In the different experimental modalities, the promoting effect was associated with the induction of chronic cell proliferation, the inhibition of the rapid response to the 2/3 partial hepatectomy and the mitotic circadian rhythm normally present during liver regeneration. It is concluded that the promotion mechanism could consist in disturbing the mitotic control in order to maintain, for a long time, a chronic low level of cell proliferation permitting the selective growth of preneoplastic cells and their subsequent transformation.

Animals↗

PubMed1999

2-acetaminofluorene blocks cell cycle progression after hepatectomy by p21 induction and lack of cyclin E expression.

In the Solt-Faber model DENA and 2-Acetaminofluorene (AAF) treatment combined with hepatectomy induces hepatocellular carcinoma in rats. In this model AAF blocks proliferation of hepatocytes, while oval cells restore liver mass. Here we studied the molecular mechanism involved in blocking AAF-dependent cell cycle progression of hepatocytes. AAF inhibits cell proliferation of hepatocytes shown by the lack of Cyclin E expression before the G1/S phase restriction point. Immunfluorescence studies revealed that Cyclin E positive signals were restricted to oval cells, while hepatocytes remained negative. Additionally, AAF treatment induces strong nuclear p53 expression which is associated with increased p21 mRNA levels. Inhibition of active Cyclin/CdK (cyclin dependent kinase) complexes is reflected in AAF-treated animals by decreased RB expression and phosphorylation. The decrease in RB expression and phosphorylation, which is essential in triggering DNA synthesis and Cyclin A expression, leads to a deficiency in transcriptionally active E2F complex formation after hepatectomy. Thus, two molecular explanations are evident to account for AAF-dependent cell cycle progression of hepatocytes in vivo: first, induction of p53 expression which leads to higher p21 mRNA levels, and second, a lack of Cyclin E expression at the G1/S phase restriction point after hepatectomy.

2-Acetylaminofluorene↗

PubMed1973

A study of some enzymes of glycerolipid biosynthesis in rat liver after subtotal hepatectomy.

1. The accumulation of triglyceride in the liver remnant after subtotal hepatectomy (removal of 82% of the liver) exceeded that described for partial hepatectomy (removal of 70% of the liver). 2. Palmitoyl-CoA synthetase, glycerol phosphate acyltransferase and diglyceride acyltransferase activities were measured in the microsomal fraction, and phosphatidate phosphohydrolase activity was measured in the particle-free supernatant fraction, prepared from the liver remnant at various times after subtotal hepatectomy. 3. The only enzyme showing a significant change in specific activity was phosphatidate phosphohydrolase. The specific activity was approximately fivefold that of the control value at 6h after operation and threefold that of the control at 10, 16 and 24h after operation. A smaller increase in the specific activity of the enzyme in sham-operated animals occurred only at 6h after operation. 4. However, at this time the total phosphohydrolase activity of the remaining liver in the sham-operated rats was approximately threefold that in hepatectomized rats. 5. Injection of actinomycin D prevented the increase in activity of phosphatidate phosphohydrolase but did not prevent the accumulation of triglyceride.

Acyltransferases↗

PubMed1975

Increased synthesis of low-molecular-weight nuclear ribonucleic acids of rat liver after gamma irradiation and hepatectomy.

Incorporation of [3H]orotic acid into low-molecular-weight nRNA of rat liver, fractionated on polyacrylamide gels, increased 6-12h after partial hepatectomy and 6h after gamma-irridation at 2000 R. The incorporation of orotic acid was particularly increased into the 4.5S, 5S and approx. 10S nRNA fractions. If the irradiation was given after 6h of regeneration and RNA was isolated from the nucleus 12h after hepatectomy then the incorporation of orotic acid into these low-molecular-weight nRNA components was greater than after hepatectomy or irradiation alone.

Animals↗

PubMed1990

Studies on the hyperplasia ('regeneration') of the rat liver following partial hepatectomy. Changes in lipid peroxidation and general biochemical aspects.

Using the experimental model of partial hepatectomy in the rat, we have examined the relationship between cell division and lipid peroxidation activity. In rats entrained to a regime of 12 h light/12 h dark and with a fixed 8 h feeding period in the dark phase, partial hepatectomy is followed by a rapid regeneration of liver mass with cycles of synchronized cell division at 24 h intervals. The latter phenomenon is indicated in this study by pulses of thymidine kinase activity having maxima at 24 h, 48 h and 72 h after partial hepatectomy. Microsomes prepared from regenerating livers show changes in lipid peroxidation activity (induced by NADPH/ADP/iron or by ascorbate/iron), which is significantly decreased relative to that in microsomes from sham-operated controls, again at 24 h, 48 h and 72 h after the operation. This phenomenon has been investigated with regard to possible underlying changes in the content of microsomal fatty acids, the microsomal enzymes NADPH:cytochrome c reductase and cytochrome P-450, and the physiological microsomal antioxidant alpha-tocopherol. The cycles of decreased lipid peroxidation activity are apparently due, at least in part, to changes in microsomal alpha-tocopherol content that are closely associated in time with thymidine kinase activity.

Animals↗