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PubMed1991

[Enhancement of selective drug accumulation and retention in normal and regenerating liver by the use of lipiodol in portal venous infusion in rats].

We studied selective accumulation and retention of lipiodol (LP) and anticancer agents in normal and regenerating liver tissue following portal infusion in rats. Total concentration of Aclarubicin (ACR) and its metabolites in liver tissue was higher in ACR + LP portal infusion group than in ACR portal infusion group both in normal and regenerating liver, concentration of active metabolites of ACR was higher in ACR portal infusion group than in ACR peripheral infusion group. Much higher concentration was found in ACR + LP portal infusion group. Histologic examination revealed more toxic effect on regenerating liver in ACR portal infusion group than in ACR + LP portal infusion group. Oil red staining demonstrated the retention of lipiodol more than 7 days following intraportal infusion in regenerating liver tissue. This study confirms that the ACR + LP portal infusion induces selective accumulation and long-term retention in normal and regenerating liver tissue, and may enhance the antitumor effect of drugs.

Aclarubicin↗
PubMed1989

Course of liver regeneration after partial hepatectomy in rats treated with dialysates obtained 17 hours after partial hepatectomy.

Various theories have been put forward to explain the regenerative capacity of liver tissue induce by partial hepatectomy (PH). One of them presumes the existence of humoral factors stimulating proliferation of the liver tissue. We evaluated the course of liver regeneration after 65-70% PH as influenced by dialysates (DIA) of the organs of a rat killed 17 h after PH. In addition to kidney DIA, we were particularly interested in the effect of liver and spleen DIA. The experiments were carried out on rats weighting 310-370 g. Kidney, liver or spleen dialysate was administered subcutaneously and the rats were killed 12 or 24 h later by exsanguination from the abdominal aorta. In further rats, PH was performed 24 h after administering DIA and the rat were killed 18, 24, 30, 48 and 72 h after the operation. The initiation of liver regeneration was stimulated by all the given DIA, but especially by liver DIA. The faster onset of liver regeneration 18 h after PH in rats given spleen DIA is interesting. DIA did not greatly affect the hepatocytes of intact liver, but accelerated the initiation of liver regeneration after PH by synchronizing the cell cycle of proliferating hepatocytes. DIA obtained 17 h after PH contained substances which primarily stimulated liver DNA synthesis. From the changes in inhibition of the migration of spleen macrophages in the medium containing liver antigens, and from the circulating immunocomplex values, we conclude that DIA activation of the immune system, a well as the hepatic stimulator substance contained in the DIA, participates in acceleration of the liver regeneration process.

Animals↗
PubMed1989

Heterogeneous activation of protein kinase C during rat liver regeneration induced by carbon tetrachloride administration.

During rat liver regeneration induced by carbon tetrachloride administration, the protein kinase C alpha subspecies was activated in a heterogeneous fashion, a higher number of hepatocytes expressing the protein kinase C alpha subspecies being detected in the pericentral zone than in the periportal zone. This zonal heterogeneity became maximal at 24 h after the treatment. The distribution of hepatocytes expressing the protein kinase C alpha subspecies was roughly coincident with that of hepatocytes exhibiting DNA synthesis. These results suggest that protein kinase C may play a crucial role in liver regeneration.

Animals↗
PubMed1976

[Cytological analysis of the intact and regenerating liver of different strains of rats].

Comparative cytological studies were conducted on control and regenerating liver of two strains (August and Cotton) of rats, 2/3 of the liver was resected; 5 or 6 animals were sacrificed at each of the following postoperative periods: in 30 hours, 3, 8, 42 and 120 days. The number of binuclear cells, the size of mononuclear hepatocytes and their nuclei, the mitotic activity, and ploidity of hepatocytes were determined. The intact and regenerating liver of the August rats differed from the intact and regenerating liver of the Cotton rats by a number of cytological indices, excluding the mitotic activity. A conclusion was drawn that the observed interstrain differences in the cytological indices providing regeneration of the liver after resection in the August and Cotton rats depended on the genotype of the given strain.

Animals↗
PubMed2003

Significant role of middle hepatic vein in remnant liver regeneration of right-lobe living donors.

For adult patients with end-stage liver disease, living-donor liver transplantation (LDLT) of right-lobe grafts with or without the middle hepatic vein (MHV) has been increasingly used in recent years. We investigated the role of the MHV in donor remnant liver regeneration after right-lobe LDLT, which has not been described in previous studies. A total of eight living donors were included in this study of right-lobe LDLT. Four donors underwent right lobectomy (without MHV), and the remaining four underwent extended right lobectomy (with MHV). Regeneration of the donor remnant liver was assessed by volumetric computed tomography studies before and 90 days after LDLT. Comparison between the right-lobe and extended right-lobe donors did not show a clear-cut difference in the net increase of remnant liver volume at 3 months. However, the mean volume increase of the medial segment at the 90th postoperative day was 7% in the extended right-lobe donors and 61% in the right-lobe donors, showing a lower value in the remnant livers without MHV. The MHV plays a specific role in remnant liver regeneration of right-lobe living donors. We expect that this knowledge will contribute to securing a margin of safety in right-lobe LDLT.

Adult↗
PubMed2006

Expression of anti-apoptotic protein, Bcl-2, in liver regeneration after a partial hepatectomy.

BACKGROUND: Although Bcl-2 is well known to have anti-apoptotic activities in vitro and in vivo, the role of Bcl-2 relating to liver regeneration remains controversial. The aim of this study was to document the effect of Bcl-2 expression on liver regeneration in rats undergoing a partial hepatectomy. MATERIAL AND METHODS: Adult male Wistar rats (n = 4/group) at 72 h before undergoing a 70% partial hepatectomy (PH) were administered 1 x 10(9) plaque-forming units of adenovirus vector encoding either human Bcl-2 (group 1) or LacZ (group 2) intravenously and were sacrificed at 0, 12 h, and at 1, 2, 3, 7, 14, and 21 days postoperatively. In group 3, normal saline was injected instead of adenovirus vector. Liver regeneration was monitored by measuring the restituted liver mass and proliferating cell nuclear antigen (PCNA) immunostaining. The incidence of apoptosis in the liver was analyzed by the immunohistochemical detection of single-stranded DNA at 14 and 21 days postoperatively. RESULTS: The restituted liver mass showed significantly higher values in group 1 (26.1 +/- 7.2%) than in group 2 (14.7 +/- 6.8%) and 3 (13.6 +/- 5.0%) at 1 day after PH (P < 0.05). The PCNA labeling index was significantly higher in group 1 (47.2 +/- 9.9%) than in groups 2 (19.0 +/- 7.8%) and 3 (19.2 +/- 15.2%) at 1 day after a partial hepatectomy (P < 0.05). The hepatocyte growth factor (HGF) mRNA expression was significantly lower in group 1 than in group 2 at 12 h after PH (P < 0.05). The number of single-stranded DNA-positive cells decreased significantly more in group 1 (5.67 +/- 1.53 positive cells/10 fields per tissue) than those in group 2 (18.33 +/- 7.57 positive cells/10 fields per tissue) at 14 days after PH. CONCLUSIONS: These results thus indicated that an overexpression of anti-apoptotic protein Bcl-2 does not necessarily have an anti-apoptotic effect on liver regeneration but appears to have a pro-proliferative effect in the early phase of liver regeneration.

Adenoviridae↗
PubMed2001

Angiotensin-converting enzyme inhibition by lisinopril enhances liver regeneration in rats.

Bradykinin has been reported to act as a growth factor for fibroblasts, mesangial cells and keratinocytes. Recently, we reported that bradykinin augments liver regeneration after partial hepatectomy in rats. Angiotensin-converting enzyme (ACE) is also a powerful bradykinin-degrading enzyme. We have investigated the effect of ACE inhibition by lisinopril on liver regeneration after partial hepatectomy. Adult male Wistar rats underwent 70% partial hepatectomy (PH). The animals received lisinopril at a dose of 1 mg kg body weight(-1) day(-1), or saline solution, intraperitoneally, for 5 days before hepatectomy, and daily after surgery. Four to six animals from the lisinopril and saline groups were sacrificed at 12, 24, 36, 48, 72, and 120 h after PH. Liver regeneration was evaluated by immunohistochemical staining for proliferating cell nuclear antigen using the PC-10 monoclonal antibody. The value for the lisinopril-treated group was three-fold above the corresponding control at 12 h after PH (P<0.001), remaining elevated at approximately two-fold above control values at 24, 36, 48 (P<0.001), and at 72 h (P<0.01) after PH, but values did not reach statistical difference at 120 h after PH. Plasma ACE activity measured by radioenzymatic assay was significantly higher in the saline group than in the lisinopril-treated group (P<0.001), with 81% ACE inhibition. The present study shows that plasma ACE inhibition enhances liver regeneration after PH in rats. Since it was reported that bradykinin also augments liver regeneration after PH, this may explain the liver growth stimulating effect of ACE inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Cyclin A is present in the endocytic compartment of rat liver cells and increases during liver regeneration.

Recent studies have implicated the cell cycle kinase cdc2 and cyclin A in the inhibition of the fusion of endocytic vesicles in vitro during mitosis. However, the presence of cyclins or their associated cyclin dependent kinases (cdks) in the endocytic fractions have not been reported. Using Western-blotting and immunocytochemistry approaches with different anticyclin A antibodies we have detected cyclin A in the endocytic compartment of the rat liver. During the pre-replicative phase of liver regeneration the amount of cyclin A in endosomes increases significantly with a peak around 12 hours after partial hepatectomy. Cyclin A-dependent kinases, cdc2 and cdk2, were also found in isolated endosome fractions, showing a distinct kinetics of accumulation during the regenerative period. Finally, histone H1 kinase activity was detected associated with cyclin A in endocytic vesicles and increased in regenerating liver. These results suggest that changes in the organization and in the function of the endocytic compartment during the hepatocellular proliferation may be modulated by proteins involved in the regulation of the cell cycle.

Animals↗
PubMed2001

Normal liver regeneration in p50/nuclear factor kappaB1 knockout mice.

Nuclear factor kappaB (NF-kappaB) is rapidly activated during liver regeneration following partial hepatectomy or carbon tetrachloride (CCl(4))-mediated liver injury and is felt to be important in the antiapoptotic and regenerative responses. After partial hepatectomy, livers of mice deficient in the p50 subunit of NF-kappaB (p50(-/-)) showed a loss of NF-kappaB and decreased STAT3 transcription factor DNA binding activities. However, nuclear levels of the NF-kappaB p65 subunit were increased and peaked earlier in p50(-/-) livers. Both messenger RNA and cytoplasmic protein levels of the NF-kappaB inhibitor IkappaBalpha were lower in p50(-/-) livers, potentially accounting for the increase in p65 protein. Small effects on gene expression posthepatectomy were observed in p50(-/-) livers, but no effects were seen on hepatocyte DNA synthetic or mitotic responses, serum enzyme levels, or overall liver mass restoration. After CCl(4) treatment, hepatocyte DNA synthesis and mitosis and serum enzyme levels were similar in p50(-/-) and p50(+/+) mice, and histologic analysis indicated a slight decrease in overall damage in p50(-/-) livers. After injection of Fas antibody, p50(-/-) livers showed an earlier onset of nuclear changes consistent with apoptosis. These data indicate that absence of p50 affects certain protein and gene activation pathways following partial hepatectomy, CCl(4), and Fas treatment but does not impair overall liver regeneration. Interleukin 6 (IL-6) levels were reduced but still adequate to support regeneration. We hypothesize that increased levels of the NF-kappaB p65 subunit in p50(-/-) livers may provide compensation for the absence of p50, thereby allowing normal liver regeneration and repair following liver injury.

Alanine Transaminase↗
PubMed1995

A single intraportal administration of follistatin accelerates liver regeneration in partially hepatectomized rats.

BACKGROUND/AIMS: Activin A is an autocrine negative regulator of DNA synthesis in rat hepatocytes and is expressed in remnant liver after partial hepatectomy. To determine the role of activin A in liver regeneration, the effects of exogenous follistatin, which blocks the action of activin A, were examined. METHODS: Human recombinant follistatin was infused into the portal vein immediately after 70% hepatectomy. Changes in body weight, remnant liver weight, liver regeneration rate, and nuclear bromodeoxyuridine labeling were measured. RESULTS: In control rats, nuclear labeling was observed at 24 hours and peaked at 36 hours after the hepatectomy. In follistatin-treated rats, nuclear labeling was first observed after 18 hours and was significantly (P < 0.05) greater than that in control rats at 24 hours. In follistatin-treated rats, both remnant liver weight and liver regeneration rate were significantly greater at 120 hours. Serum concentrations of albumin and glucose remained reduced for up to 120 hours in control rats but recovered in follistatin-treated rats. CONCLUSIONS: A single administration of follistatin accelerates the initial round of DNA synthesis after partial hepatectomy. Activin A produced in remnant liver may exert tonic inhibitory effect on liver regeneration. Follistatin may be useful as a potential therapeutic agent to promote liver regeneration.

Activins↗
PubMedDate not supplied

Ultrasound and biochemical evaluation of liver regeneration process after resections for primary and metastatic tumors.

BACKGROUND/AIMS: The liver regeneration process after resective procedures is an important clinical problem especially in view of the growing population of patients requiring liver transplantations or undergoing resective procedures as well as those with toxic or viral liver injures. The aim of the study was to analyze liver regeneration potential using ultrasound examination, and liver function biochemical tests in the patients after liver resections. METHODOLOGY: Twenty-one patients with primary or metastatic liver cancer were included in the study (17 males, 4 females, mean age: 59.8, SD 10.3). The patients were undergoing gastrointestinal tract primary tumor resections with extended lymphadenectomy and liver metastatic tumor excisions. Liver volume was measured postoperatively in the follow-up ultrasound examinations and biochemical tests were performed before and after the procedure. Liver function and activity of p-450 cytochrome was tested with IRIS 13C stable isotope breath analyzer. RESULTS: The mean time of follow-up was 12.6 months (SD 7.8) during which volume of liver increased on average in the first five months to 105.7, 112.1, 125.7, 131.2, and 138.4% of the immediate postoperative value. Biochemical parameters returned to normal after 2-3 weeks. Four patients in whom liver failed to regenerate died due to cancer spread in the mean time of 6.5 months. CONCLUSIONS: Liver has tremendous regeneration potential. In spite of this fact, extended hepatectomies affect largely the functional status of residual parenchyma which may lead to a fatal outcome.

Adult↗
PubMed1994

[Modification of surface phenotype and function in intrahepatic lymphocytes during liver regeneration after partial hepatectomy].

In the intrahepatic lymphocyte fraction (IHL) of mice whose livers have been perfused by Ca+2 and Mg+2 free Hank's balance salt solution, flow cytometric analysis reveals various cells similar to those found in the spleen (CD3+ cell, CD4+ cell, CD8+ cell, alpha beta TCR+ cell, gamma delta TCR+ cell, Thy1.2+ cell, B220+ cell and asialo-Gm1+ cell). The cytotoxic activity against YAC-1 cells in IHL is significantly higher than that in spleen cells. Furthermore, IHL has cytolytic activity against syngeneic thymoma BW5147 cells which is not found in spleen cells. Both cytotoxic activities of IHL are greatly weakened by the pretreatment of IHL with anti asialo-Gm1 Ab and rabbit complement. During liver regeneration after a partial hepatectomy, the percentages of lymphocyte subsets of IHL such as alpha beta TCR+ cells, gamma delta TCR+ cells and asialo-Gm1+ cells transiently increase 2 days after the partial hepatectomy and their cytotoxic activities against YAC-1 and BW5147 cells also reach a peak at that time. It is well known that the peak of mitotic index in regenerating parenchymal liver cells peaks 2 days after a partial hepatectomy and that the number of Pit cells peaks 10 to 14 days after. Compared with the time for reaching the highest mitotic index in regenerating parenchymal liver cells, the proliferation of Pit cells comes very late. It has not been clear which proliferation process in parenchymal liver cells is suppressed by activated Pit cells. Our findings in this paper reveal that the percentages and the cytotoxic activities of asialo-Gm1+ cells in IHL reach their peak 2 days after an operation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Sequential analysis of hepatic carcinogenesis: the comparative architecture of preneoplastic, malignant, prenatal, postnatal and regenerating liver.

The organizational pattern of hepatocytes in hyperplastic nodules, probable precursors of hepatocellular carcinoma, was examined sequentially at different stages in the carcinogenic process, and compared with the patterns in hepatocellular carcinomas, in developing liver and in regnerating liver. Scanning as well as transmission electron microscopy, and histochemistry with light microscopy were used. The hepatocytes in the hyperplastic lesions were arranged in plates 2 or more cells thick and glands, in contrast to the one-cell-thick plates of hepatocytes in normal mature liver, and showed unusualy separation from eachother, with irregularly dilated bile canaliculi. The organizational pattern found in the hyperplastic lesions shared properties with developing liver in the perinatal period, regenerating liver following the peak of cell division, and some hepatocellular carcinomas. Unlike the normal, in which there is a highly predictable time scale for change, an apparent delay or interruption of maturation may be of importance in lesions that persist and ultimately evolve into hepatocullular carcinoma.

Animals↗
PubMed1992

Effect of Gomisin A (TJN-101) on liver regeneration.

We studied the effect of TJN-101, a lignan component of Schisandra fruits (Schisandrae fructus), on liver regeneration after partial hepatectomy. TJN-101 was given orally to male Wistar rats 30 min before partial hepatectomy. The mitotic index and the level of DNA synthesis increased after partial hepatectomy and their increase was significantly enhanced by TJN-101. Ornithine decarboxylase (ODC) activity increased in the early stages of liver regeneration and it was also significantly enhanced by TJN-101. Besides, TJN-101 enhanced the increase in hepatic putrescine. These results suggest that TJN-101 stimulates liver regeneration after partial hepatectomy by enhancing ODC activity, which is an important biochemical event in the early stages of liver regeneration.

Animals↗
PubMedDate not supplied

Comparison of the effects of bischolylglycinatechloro-platinum(II) versus cisplatin on liver regeneration after partial hepatectomy.

BACKGROUND: Regional chemotherapy by intraportal administration has been envisaged as a useful strategy to prevent the high rate of recurrence after surgical removal of single liver tumors, even though it may inhibit liver regeneration. New cytostatic drugs, such as Bamet-H2-Na[Pt(cholylglycinate-O,N) (cholylglycinate-O) Cl]- have been developed to enhance the liver organotropism of antiproliferative agents. The aim of the present study was to compare the effects of Bamet-H2 and cisplatin on liver regeneration. MATERIALS AND METHODS: The ability of both drugs to inhibit liver cell proliferation was investigated using rat hepatocytes in primary culture. Two-thirds partially hepatectomized mice were used to measure the effects of glycocholic acid, cisplatin and Bamet-H2 on DNA synthesis by the regenerating liver in vivo. RESULTS: Up to 300 microM glycocholic acid, no effect on the growth of rat hepatocytes in primary culture was observed. By contrast, similar dose-dependent in vitro cytostatic effects of cisplatin and Bamet-H2 were found. No effect on mouse liver regeneration was found in animals receiving glycocholic acid. By contrast, both cisplatin and Bamet-H2 were found to induce a significant inhibition of DNA synthesis and slower recovery of liver mass. The effect of cisplatin was significantly stronger than that induced by Bamet-H2. Differences between these two compounds were also observed regarding the content of the drug in several tissues at short- and mid-term. Both drugs were highly concentrated in the liver and kidney, with minor distribution in other tissues at 8 hours after the last injection of the drug. However, Bamet-H2 was more efficiently eliminated from the body in 5 days. Moreover, higher toxicity and lower survival were observed in the group of animals treated with cisplatin as compared to Bamet-H2. CONCLUSIONS: Our results indicate that in agreement with the previously reported effects on several tumor cells lines, cisplatin and Bamet-H2 are similarly efficient as cytostatic drugs in liver cells when these are continuously exposed to the compounds in vitro. However, in the in vivo situation Bamet-H2 is better tolerated by the animals and induces less inhibition of liver regeneration than cisplatin. This is probably due to the enhanced biliary elimination of Bamet-H2.

Animals↗
PubMed1996

Chronic ethanol administration to rats decreases receptor-operated mobilization of intracellular ionic calcium in cultured hepatocytes and inhibits 1,4,5-inositol trisphosphate production: relevance to impaired liver regeneration.

We tested the hypothesis that ethanol impairs liver regeneration by abrogating receptor-mediated elevation of cytosolic free calcium ([Ca2+]i). In rats fed for 16 weeks with ethanol, hepatocellular proliferation induced by partial hepatectomy was greatly impaired. Similarly, EGF-induced DNA synthesis was reduced in cultured hepatocytes from ethanol-fed rats. There was no change in the number or affinity of EGF receptors on hepatocytes from ethanol-fed rats. Despite this, EGF-mediated production of inositol 1,4,5-trisphosphate (Ins[1,4,5]P3) was lower in hepatocytes from ethanol-fed rats, and the EGF-induced [Ca2+]i transient appeared to be abrogated. When vasopressin or phenylephrine were used as cell surface receptor ligands, hepatocytes cultured from ethanol-fed rats exhibited major reductions in Ins(1,4,5)P3 synthesis. This was associated with greatly truncated [Ca2+]i transients. These changes were not due to an effect on the Ins(1,4,5)P3 receptor on the endoplasmic reticulum or to a decrease in the size of the Ins(1,4,5)P3-mobilizable intracellular Ca+2 store. Further, mobilization of the same Ca2+ store by 2,5-di-tert-butylhydroquinone or thapsigargin restored the ability of hepatocytes from ethanol-fed rats to proliferate when exposed to EGF. It is concluded that chronic ethanol consumption inhibits liver regeneration by a mechanism that is, at least partly, the result of impaired receptor-operated [Ca2+]i signaling due to reduced generation of Ins(1,4,5)P3.

Alcoholism↗
PubMed1989

Course of liver regeneration after partial hepatectomy in rats treated with dialysates of intact organs.

A number of growth phenomena observed in vitro have shown that cells, at high densities, produce and release substances which, when they have reached a given concentration, arrest further growth. In vivo, these possibilities can be studied on the model of rapid regeneration of the rat liver after 65-70% partial hepatectomy (PH). We evaluated the course of liver regeneration after PH in animals treated with dialysates (DIA) of intact rat tissues. In addition to kidney and lymph node DIA, we were particularly interested in the effect of liver and spleen DIA. The experiments were carried out on male rats weighing 210-240 g. The relevant DIA was administered 24 h prior to PH; the controls were given physiological saline. The animals were killed just before PH and 24, 48, 30 and 72 h and 14 days after. DIA obtained from intact liver tissue inhibited the regeneration process induced by PH and its effect persisted 48 h after PH. Compared with the controls and with the rats given kidney DIA, DNA synthesis in the liver 24 h after PH was reduced to 77%. After spleen DIA, several (still hypothetical) factors probably acted together synergically (factors belonging to the immune system--RES--and spleen-produced factors capable of promoting proliferation of the hepatocytes--the "portal blood factor"). We arrived at this conclusion from an evaluation of liver DNA synthesis 24 h after 24h after PH, when synthesis was altogether markedly raised, but attained far higher values after the administration of spleen DIA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

[The effects of protein and amino acids on DNA synthesis in regenerating liver].

In order to estimate the effects of protein and amino acids on regenerating liver, the induction of enzymes involved in synthesis of DNA was studied in rats fed protein free diet. In the regenerating livers of rats of the protein free diet, increase of liver weight and DNA content were stopped 48 hours after hepatectomy, and induction of DNA synthesizing enzymes such as dCMP deaminase, ribonucleotide reductase, and thymidine kinase were depressed and shortened. On the other hand, induction of protein or RNA synthesizing enzymes such as polyamine, ornithine decarboxylase, and tyrosine aminotransferase were not depressed by protein deprivation. The results indicate that protein deprivation inhibits the DNA synthesizing enzymes specifically, and regenerating liver cells can not enter S phase of cell cycle. When rats were maintained solely by total parenteral nutrition after hepatectomy, amino acids were essential for induction of DNA synthesizing enzymes. In particular, induction of these enzymes were regulated by 7 amino acids include Val, Leu, Ile, Met, Trp, Phe, and Thr, and most of these plasma amino acid levels were depressed after hepatectomy. By administration of amino acids for 12 hours just after hepatectomy, the DNA synthesizing enzymes were almost normally induced. This suggests that amino acids administration just after hepatectomy is effective to induce the DNA synthesizing enzymes for hepatic regeneration.

Amino Acids↗