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PubMed1990

Experimental colorectal liver metastases. Influence of sex, immunological status and liver regeneration.

The liver is the most frequent site of metastases from colon cancer. To improve our knowledge of liver metastases and to develop new adjuvant therapies, a good animal model is necessary. The aims of this study were to obtain a model of liver metastases with intraportal injection of colon adrenocarcinoma cell aggregates (DHDK12 cell line) and to study the effect of various factors, i.e., sex, liver regeneration and immunosuppression, on the development of liver metastasis. Cell aggregates were injected into the portal vein of 59 syngenic male and female BD IX rats following randomization into three groups. Group 1, (control 12 males and 10 females) received only cell aggregates; group 2 (12 males and 10 females) underwent a 70% hepatectomy before cell injection; group 3 (15 males and 10 females) received cyclosporin A injections at a dose of 10 mg/kg per day for 28 days following cell injection. Autopsy was performed at 10 weeks. Liver metastases were more frequent in the male rats in group 3 than in those in group 1 (80% vs. 30%, p less than 0.04). The rate of liver metastases in females was not increased by immunosuppression (22.2% vs. 12.5%, N.S.). Liver resection (group 2) did not significantly modify the incidence of liver metastasis. No female had liver metastases in this group. This relatively simple model rapidly produces liver metastasis with a high yield, but only in male rats. Besides sexual factors, immunosuppression also increased the rate of experimental liver metastasis, while liver regeneration failed to do so.

Adenocarcinoma↗
PubMed1990

Liver regeneration and restoration of liver function after partial hepatectomy in patients with liver tumors.

Liver regeneration and restoration of liver function were studied in six patients who underwent partial hepatectomy with removal of 30-70% of the liver. Liver volume and liver regeneration were studied by single-photon computed tomography (SPECT), using 99mTc-colloid as tracer. The method was assessed in 11 patients by comparing the pre- and post-operative volume measurements with the volume of the resected liver mass. The correlation coefficient between these methods was 0.899 (P less than 0.01). Liver function was determined by measuring the galactose elimination capacity and the caffeine clearance. After a postoperative follow-up period of 50 days the liver had regenerated maximally to a volume of 75 +/- 2% of the preoperative liver mass. Maximal restoration of liver function was achieved 120 days after operation and amounted to 75 +/- 10% for the caffeine clearance and to 100 +/- 25% for the galactose elimination capacity. This study shows that SPECT is a useful method for assessing liver regeneration in patients after partial hepatectomy. Our study furthermore shows that caffeine clearance correlates well with total liver volume, whereas the galactose elimination capacity overestimates total liver volume after partial hepatectomy.

Adult↗
PubMed1993

Augmentation of liver regeneration with glucagon after partial hepatectomy in rats.

The direct stimulating effect of glucagon on partially hepatectomized rats was studied. Following a 70% hepatectomy, male Wister rats were divided into three groups. Group I received glucagon 0.8 mg/kg/day; group II received hydrocortisone 10 mg/kg/day; and group III received normal saline as a control. Their blood sugar levels and food intake were not significantly different. After one week, the regenerated livers in group I were larger (9.69 +/- 0.30 cm3 vs 8.29 +/- 0.34 cm3 in group II and 8.20 +/- 0.10 cm3 in group III), and heavier (9.83 +/- 0.28 g vs 8.52 +/- 0.33 g in group II and 8.75 +/- 0.21 g in group III) than those in the other two groups. The mitotic index in group I was also higher. The results suggest that glucagon has a direct hepatotrophic effect and enhances regeneration of the liver in rats.

Animals↗
PubMed1996

[Expression and significance of PKC alpha in regenerating liver of rats after partial hepatectomy and CCl4 administration].

Immunocytochemistry showed PKC alpha-positive hepatocytes around portal area after two-thirds PH, and they were distributed diffusely in lobules, and reached a peak in number 12 hrs. It's location was not only on membrane facing sinusoid or lateral membrane but also in rough endoplasmic reticulum or in cytosol. Combined technique of immunocytochemistry and ARG revealed presence of (H)-grains at 24 hrs in hepatocytes around the portal tract. PKC alpha was expressed in hepatocytes around central necrosis 6 hrs after administration of CCl4 and its immunoreactivity was visible not only on cytoplasmic membrane but also in cytoplasm, and PKC alpha-positive hepatocytes reached a peak in number at 24 hrs. (H)-labeled hepatocytes were observed around central necrosis at 48 hrs, and AFP was expressed in the same area at 96 hrs. These findings suggest that PKC alpha is expressed in proliferating lesion after PH or administration of CCl4, and that PKC alpha may make an important role in the early phase of cell proliferation, then it is closely associated with liver regeneration.

Animals↗
PubMed1984

[Liver regeneration and the immune system. II. Suppressor activities of lymphocytes activated in vivo by liver regeneration and their genetic control].

The lymph node cells (LNC) activated in vivo by liver regeneration following partial hepatectomy of mice (pLNC: primed lymph node cells) respond to regenerating liver cells in vitro with typical secondary immune response characteristics (as shown in Paper I). These lymph node cells activated in vivo suppress the proliferation of responder lymphocytes cultured with mitomycin C (MMC)-treated regenerating syngeneic liver cells (sMLHLR). The suppressive activity was already present in LNC 4 days after partial hepatectomy and remained unchanged for at least 16 days. These pLNC were effective not only on sMLHLR but also on syngeneic mixed lymphocyte culture (sMLR) and allogeneic mixed lymphocyte culture (MLR), of which responder cells share I-A (I-B) subregions of MHC with pLNC. The pLNC restimulated in vitro with regenerating liver cells (ppLNC: in vitro reactivated pLNC) suppress the proliferation of syngeneic responder cells in sMLR, but not of cells from congeneic mice differing from the ppLNC at a cluster of genes linked to the Ig locus. Thus the suppressive activity of pLNC is controlled by the I-A (I-B) subregions of the MHC and that of ppLNC by genes in the Ig region.

Animals↗
PubMed1981

[Relation between membrane potential changes and DNA, RNA and protein synthesis in regenerating liver cells after partial hepatectomy].

Variations in the membrane potential and in DNA, RNA and protein synthesis were studied in experiments on rats at varying times after hepatectomy. Hyperpolarization of the hepatocyte plasmatic membrane was shown to develop during liver regeneration along with activation of DNA, RNA and protein synthesis. Actinomycin D prevented the development of hyperpolarization and activation of RNA and protein synthesis. Administration of liver filtrates from hepatectomized rats to intact recipients induced hyperpolarization of liver cells. Activation of protein biosynthesis following hepatectomy resulted in hyperpolarization of the cell membrane, this action being mediated via formation of a specific membrane-active factor.

Animals↗
PubMed1987

Relationship between biliary calcium and bile acid secretion in the regenerating liver of the rat.

Biliary calcium secretion during liver regeneration following two-thirds hepatectomy was studied in Wistar rats. Calcium output per 100 g body weight was significantly reduced at 24 h post-hepatectomy but not at other times. Values per gram of liver were significantly increased at 48 h and 96 h. A significant relationship was found between bile acid output and calcium output into bile both in controls and hepatectomized animals. The number of nmol of calcium secreted per nmol of bile acids was increased at 24 h post-hepatectomy parallel to an increased choleretic capacity of bile acids and a decrease in the fraction of bile acid independent flow. Our data confirm that bile acid secretion is an important determinant in the secretion of calcium into bile after partial hepatectomy in the rat.

Animals↗
PubMed2003

Jun N-terminal kinase activation and upregulation of p53 and p21(WAF1/CIP1) in selenite-induced apoptosis of regenerating liver.

To investigate apoptosis induced by selenite in hepatocytes in vivo, rats received a single injection of sodium selenite immediately after partial hepatectomy. Characteristic DNA fragmentation in gel electrophoresis and in situ end-labeling and the increase in caspase-3 activity were observed at 4 h after partial hepatectomy with selenite injection. The activation of Jun N-terminal kinase (JNK) was observed as early as 15 min and increased to about 10-fold the maximal level of the control at 1 and 2 h after partial hepatectomy in selenite-injected rats, while a transient increase was observed at 1 h in the control. Western blot analysis revealed that the c-Jun and the phosphorylated c-Jun protein markedly increased after 30 min and reached a maximal level at 1 and 2 h after partial hepatectomy with selenite injection, although c-Jun and a faint band of the phosphorylated c-Jun were observed after 1 h in the control. The levels of c-jun mRNA and c-Fos protein and mRNA in selenite-injected rats also increased more than in the control. The rise in the p53 protein level after partial hepatectomy with selenite injection was followed by the upregulation of p21(WAF1/CIP1) mRNA and protein expression. These results suggested that selenite induced apoptosis accompanied by the activation of caspase-3 and JNK and the upregulation of c-jun, c-fos, p53 and p21(WAF1/CIP1) at the early stage of liver regeneration.

Animals↗
PubMed1996

Transcriptional regulation of alpha(1b) adrenergic receptors (alpha(1b)AR) by nuclear factor 1 (NF1): a decline in the concentration of NF1 correlates with the downregulation of alpha(1b)AR gene expression in regenerating liver.

The 5' upstream region from --490 to --540 (footprint II) within the dominant P2 promoter of the rat alpha(1b) adrenergic receptor (alpha(1b)AR) gene is recognized by a sequence-specific DNA-binding protein (B. Gao, M. S. Spector, and G. Kunos, J. Biol. Chem. 270:5614-5619, 1995). This protein, detectable in Southwestern (DNA-protein) blots of crude nuclear extracts as 32- and 34-kDa bands, has been purified 6,000-fold from rat livers by DEAE-Sepharose, heparin-Sepharose, and DNA affinity chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and UV cross-linking of the purified protein indicated the same molecular mass as that in crude extracts. Methylation interference analysis revealed strong contact with a TTGGCT hexamer and weak contact with a TGGCGT hexamer in the 3' and 5' portions of footprint II, respectively. Nucleotide substitutions within these hexamers significantly reduced protein binding to footprint II and the promoter activity of P2 in Hep3B cells. The purified protein also bound to the nuclear factor 1 (NF1)/CTF consensus sequence, albeit with lower affinity. Gel mobility supershift and Western blotting (immunoblotting) analyses using an antibody against the NF1/CTF protein identified the purified 32- and 34-kDa polypeptides as NF1 or a related protein. Cotransfection into Hep3B cells or primary rat hepatocytes of cDNAs of the NF1-like proteins NF1/L, NF1/X, and NF1/Redl resulted in a three- to fivefold increase in transcription directed by wild-type P2 but not by the mutated P2. Partial hepatectomy markedly decreased the levels of NF1 in the remnant liver and its binding to P2, which paralleled declines in the rate of transcription of the alpha(1b)AR gene and in the steady-state levels of its mRNA. These observations indicate that NF1 activates transcription of the rat alpha(1b)AR gene via interacting with its P2 promoter and that a decline in the expression of NF1 is one of the mechanisms responsible for the reduced expression of the alpha(1b)AR gene during liver regeneration.

Animals↗
PubMed1997

Export of hepatitis B virus RNA on a Rev-like pathway: inhibition by the regenerating liver inhibitory factor IkappaB alpha.

Nuclear export of hepatitis B virus (HBV) RNA is mediated by a specific RNA element but, in contrast to lentivirus genomic RNA, does not depend on viral proteins. We show that nonetheless, the export of HBV RNA can be blocked by competitive inhibitors of Rev-mediated lentivirus RNA export, suggesting that the export pathways of both viral species share components and might be driven by the same nuclear export machinery. HBV RNA export is also inhibited by overexpression of IkappaB alpha, as reported previously for the export of human immunodeficiency virus RNA. Since IkappaB alpha is strongly overexpressed during liver regeneration, its inhibition of HBV RNA export might contribute to elimination or silent persistence of HBV.

Biological Transport↗
PubMedDate not supplied

[Changes in the proliferative activity of the corneal epithelium and the regenerating liver in partial splenectomy in mice].

The mitotic activity in epithelial cells of the mouse cornea was studied 4 h, 1, 2, 5, 8 and 14 days after a sham operation or partial (2/3) splenectomy. The decrease in the number of dividing cells in the corneal epithelium was observed within two days after a sham operation and within five days after partial splenectomy. On the contrary, partial hepatectomy increased the number of mitoses in the corneal epithelium. Liver regeneration against the background of a sham operation or partial splenectomy was accompanied by a lesser number of mitoses (by a factor of 2.5-4) in hepatocytes than in the animals subjected to partial hepatectomy only.

Animals↗
PubMed2005

[Liver regeneration].

The liver is one of the most complex organs in the body, containing at least seven different cell types and carrying out over 5000 functions. The liver transplantation became a known and effective method for treating its end-stage insufficiency. In response to hepatocellular damage (viral, chemical or surgical injury) the liver mounts inflammatory, regenerative and repair processes with the aim of restoring the functional liver tissue mass. Restoration or liver regeneration after a partial hepatectomy has been scientifically observed since the late nineteenth century. By definition, liver regeneration is an orchestrated response induced by specific external stimuli, involving sequential changes in gene expression, growth factor production, and morphologic structure. During this process, the liver undergoes compensatory hyperplasia in order to reestablish the optimal mass set in relationship to its body size. Many growth factors and cytokines, most notably HGF, EGF, TGF-alpha, IL-6, TNF-alpha, insulin and norepinephrine, seem to play important roles in this process.

Epidermal Growth Factor↗
PubMed1981

Synthesis of alpha-fetoprotein (AFP) and cell proliferation in regenerating livers of NMRI mice after partial hepatectomy. An immunohistochemical and autoradiographic study with 3H-thymidine.

To get more information concerning the relation between cell proliferation and the synthesis of alpha-fetoprotein (AFP), liver regeneration and AFP production was followed simultaneously in short intervals in NMRI mice after two-thirds hepatectomy using autoradiographic and immunohistochemical methods. The results indicate that AFP synthesis is not linked closely to cell proliferation in the sense that each proliferating hepatocyte synthesizes AFP during a definite phase of the cell cycle. However, AFP production, as measured by the index of anti-AFP positive hepatocytes, occurs in a very small population of parenchymal cells when the bulk of the hepatocytes has just passed the S-phase and is considered to be in the G2-, M or early G1-phase of the cell cycle when the cells are still in an undifferentiate state.

Animals↗
PubMed1978

Loss and reappearance of gap junctions in regenerating liver.

Changes in intercellular junctional morphology associated with rat liver regeneration were examined in a freeze-fracture study. After a two-thirds partial hepatectomy, both gap junctions and zonulae occludentes were drastically altered. Between 0 and 20 h after partial hepatectomy, the junctions appeared virtually unchanged. 28 h after partial hepatectomy, however, the large gap junctions usually located close to the bile canaliculi and the small gap junctions enmeshed within the strands of the zonulae occudentes completely disappeared. Although the zonulae occludentes bordering the bile canaliculi apparently remained intact, numerous strands could now be found oriented perpendicular to the canaliculi. In some instances, the membrane outside the canaliculi was extensively filled with isolated junctional strands, often forming very complex configurations. About 40 h after partial hepatectomy, very many small gap junctions reappeared in close association with the zonulae occludentes. Subsequently, gap junctions increased in size and decreased in number until about 48 h after partial hepatectomy when gap junctions were indistinguishable in size and number from those of control animals. The zonulae occludentes were again predominantly located around the canalicular margins. These studies provide further evidence for the growth of gap junctions by the accretion of particles and of small gap junctions to form large maculae.

Animals↗
PubMed2003

p18(INK4c) collaborates with other CDK-inhibitory proteins in the regenerating liver.

p18(INK4c) belongs to the family of cyclin-dependent kinase inhibitory proteins that target the cyclin-dependent kinases and inhibit their catalytic activity. The role of p18(INK4c) for cell cycle progression in vivo is characterized poorly. Therefore, we studied the expression and physiologic relevance of p18 in quiescent and proliferating hepatocytes during liver regeneration. For our analysis we used single- (p18[INK4c], p27[KIP1], p21[CIP1/WAF1]), and double-mutant (p18/p21, p18/p27) mice. p18 expression was found in quiescent hepatocytes and a slight up-regulation was evident after partial hepatectomy (PH). p18 knockout animals showed normal cell cycle progression after PH. However, when p18/p21 and p18/p27 double-mutant mice were used, differences in cell cycle progression were evident compared with wild-type (wt) and single knockout animals. In p18/p21 knockout animals, the G1 phase was shortened as evidenced by an earlier onset of cyclin D and proliferating cell nuclear antigen (PCNA) expression and cyclin-dependent kinase (CDK) activation after PH. In contrast, in p18/p27 knockout animals, the G1 phase was unchanged, but the amount of proliferating hepatocytes (5-bromo-2'-deoxyuridine [BrdU] and PCNA positive) 48 hours after PH was elevated. In conclusion, our results suggest that p18 is involved in cell cycle progression after PH. Additionally we provide evidence that timing and strength of DNA synthesis in hepatocytes after PH is regulated tightly through the collaboration of different cell cycle inhibitors.

Animals↗
PubMed1978

Effect of 5-fluorouracil on liver regeneration and metabolism after partial hepatectomy in the rat.

The effects of 5-fluorouracil (5-FU) on regenerating liver were studied after two thirds hepatectomy in rats. In Group I, 68% hepatectomy was performed. In Group II, 5-FU in a dose of 20 mg/kg was administered intravenously immediately after, 24 and 48 hours after the same hepatectomy. In Group III, the same amount of 5-FU was given after sham-operation. The mortality rates were 4.5% in Group I, 28.0% in Group II, and 0% in Group III. The treatment with 5-FU following hepatectomy caused not only suppression but delay of liver cell division. Histologic changes such as cellular degeneration, liver steatosis and dilatation of the sinusoidal space were marked and prolonged in the hepatectomy-5-FU group. The metabolic abnormalities in albumin, cholesterol, triglycedides, and phospholipids were further more profound in Group II compared to those in Group I. In Group III, moderate derangements in albumin, triglycerides and phospholipids were observed. The results may indicate that adjuvant chemotherapy with 5-FU or similar drugs immediately after partial hepatectomy in hepatoma patients should be performed with great care if necessary. Otherwise, it should not be carried out until hepatic regneration is almost completed.

Animals↗
PubMed1998

Inhibition of in vivo rat liver regeneration by 2-acetylaminofluorene affects the regulation of cell cycle-related proteins.

The effects of dietary 2-acetylaminofluorene (2-AAF) on cell cycle-related proteins was studied in regenerating livers from male Wistar rats. The levels of cyclins, cyclin dependent kinases (cdks), and related proteins were studied at different times during the first cell cycle after partial hepatectomy (PH). The frequency of proliferation cell nuclear antigen (PCNA)-positive nuclei, a marker of S phase progression, was almost zero during the first 27 hours after PH in the mitoinhibited 2-AAF-treated rats, while about 50% of the nuclei were labeled 24 hours after PH in control animals. Accordingly, Western blot tests showed markedly elevated PCNA protein levels from 18 hours to the end of S phase in untreated animals but no upregulation in response to 2-AAF. Compared with control animals, animals treated with 2-AAF showed increased levels of cdk 4 and cyclin D3 from 12 and 15 hours after PH, respectively, and altered cyclicity in cyclin D3 expression. No effects on cyclin E were observed, while the increase in cdk 2 levels in control animals during late G1/S (15-27 hours) was abolished by 2-AAF. p53 was induced by 2-AAF treatment during the same period, with a peak at 24 hours. The protein detected with p21 antibodies was highly expressed in unstimulated hepatocytes in control animals, and further increased by 2-AAF. The expression was sustained until 15 hours after PH in control rats while 2-AAF-treated animals lacked detectable protein during this period; however, a transient increase was observed at 21 hours. Thus, 2-AAF affects several parameters of cell cycle regulation of possible relevance for its inhibitory effects on hepatocyte proliferation in vivo.

2-Acetylaminofluorene↗