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PubMedDate not supplied

The liver as a potential hematolymphoid organ examined from modifications occurring in the systemic and intrahepatic hematolymphoid system during liver regeneration after partial hepatectomy.

In order to investigate whether or not the adult murine liver can function as one of the hematolymphoid organs, we studied the alteration of cellular characteristics in the systemic and intrahepatic hematolymphoid systems during liver regeneration after partial hepatectomy. Liver regeneration affects the systemic hematolymphoid system, as can been seen from the transient increase in colony forming unit in culture (CFU-C) frequency observed in the bone marrow at 20 hr and its gradual increase in the spleen up to the 6th day after partial hepatectomy. CFU-C were found not only in peripheral blood lymphocyte-rich fraction (PBL), but also in intrahepatic lymphocyte-rich fraction (IHL) of the normal adult liver. CFU-C frequency showed a weak increase in PBL and a dramatic increase, up to the 6th post-hepatectomy day, in IHL subfraction cells, forming a very strong liver association. Colonies, which were generated from IHL in a fibrin clot culture system, were mainly composed of granulocytes, macrophages and mast cells. Wheat germ agglutinin (WGA) positive cells too were detected in IHL and found to increase after partial hepatectomy. IHL of the normal liver were proliferated not only by IL-3 and GM-CSF but also by IL-2. The proliferative responses of IHL to these cytokines were further augmented on day 6 after partial hepatectomy. Similar results were obtained in peripheral blood and splenic lymphocyte-rich fractions. These observations, therefore, suggest that the adult murine liver has hematolymphoid cells as its component and has the function of a hematolymphoid organ closely associated with the systemic hematolymphoid system.

Animals↗
PubMedDate not supplied

[The effect of factors stimulating proliferation of hepatocytes on cholesterol esterification in the serum during liver regeneration].

Two-step regeneration of rat liver tissue was observed after partial hepatectomy. The first step involved mitosis of hepatocytes and the second step--division of the cells containing two nuclei and hypertrophy of hepatocytes. Both these steps of liver tissue regeneration were accompanied by hypercholesterolemia and a decrease in the cholesterol esterification activity in blood serum. The factors, stimulating hepatocyte proliferation, accelerated the reparative liver tissue regeneration due to activation of mitosis and the early division of the cells containing two nuclei. At the same time, the highest regeneration of the cholesterol esterification system was detected in circulation.

Animals↗
PubMed1987

[Immunologic properties of primary culture of regenerating liver cells in mice].

The immunologic characteristics of primary cell culture of regenerating mouse liver cells is described. The DNA synthesis of regenerating liver cells isolated after 70% partial hepatectomy was found greater than that without partial hepatectomy. Increased level of stimulated DNA synthesis was noted on 3rd day post hepatectomy, with the highest levels noted on the 4th day. The level of 3H-thymidine incorporation became apparent on day 3 of culture, reaching maximum on day 6 and gradually decreasing there after. Dexamethasone added to the medium increased the attachment rate of liver cells to the culture plate. Insulin and epidermal growth factor added to the medium did not result in any increased DNA synthesis of the liver cells at day 4 of the culture but manifested its effect at day 10. When various cells which were treated with mitomycin C were co-cultured with the liver cells, both normal and regenerating liver cells were suppressed by the addition of normal spleen cells. The degree of suppression was more marked in the culture with regenerating liver cells. When cultured with other immune competent cells, there was no significant difference between the two groups. This suggests that the suppressive activity of the immune competent cells on the cultured regenerating liver cells was not genetically determined.

Animals↗
PubMed1988

Partial hepatectomy and liver regeneration in pigs--the response to different resection sizes.

Liver regeneration has been extensively studied in the rat and dog models but pigs have seldom been used. They resemble man closely in their omnivorous diet and their gastroenterological and endocrinological responses. This paper describes techniques of 15, 50, 65, and 70% partial hepatectomy in the pig. Thymidine kinase activity and mitotic index were used as indices of liver regeneration. The timing and events of the regenerative response in the pig compared favorably with other animal models and the maximum regenerative response occurred on the third postoperative day, irrespective of the size of the partial hepatectomy. The 15% partial hepatectomy, which shows a minimal response to resection, provides a suitable "primed" model for the study of stimulatory substances.

Animals↗
PubMedDate not supplied

Effects of amino acid infusions on liver regeneration after partial hepatectomy in the rat.

Administration of solutions high in branched-chain amino acids (BCAA) has been advocated in patients with severe liver failure; however, the effect of this treatment on the process of liver regeneration is still unclear. In the present study using rats we investigated the influence on liver regeneration of infusing solutions differing in amino acid content. After 75% hepatectomy, rats were infused via jugular vein with one of the following solutions: Sol A) 10% dextrose, Sol B) 10% dextrose + 3% amino acids (22% BCAA), Sol C) 10% dextrose + 3% amino acids (35% BCAA). Liver regeneration was estimated by measuring the incorporation of 3H-thymidine into DNA at five different time points after the operation. Peak regeneration occurred earlier in rats infused with the BCAA-enriched solution compared to animals infused with the standard amino acid solution or with dextrose alone. The increased incorporation of 3H-thymidine into DNA at 24 hr in rats infused with the BCAA-enriched solution was associated with elevated plasma levels of BCAA and decreased concentrations of tyrosine, phenylalanine, and methionine in comparison with the other two treatment groups. These results suggest that liver regeneration in rats can be accelerated by administering a parenteral nutrition solution tailored to normalize the deranged pattern of plasma amino acids associated with compromised liver function.

Amino Acids, Branched-Chain↗
PubMed1993

[A study of regenerating liver protects against carbon tetrachloride injury in rat].

In our previous study we had demonstrated that regenerating liver of rats had an ability to resist CCl4 injury. In this paper, the underlying mechanism was further investigated. Hepatic stimulator substance from regenerating liver (rHSS) at different time after partial (68%) hepatectomy was extracted and assayed for its biological activity by using 3H-thymidine. The activity is approximately seven-fold as compared with the control. Then, rHSS was given to rats to observe its effect against CCl4 injury both in vivo and in vitro. The results were as follows: rHSS decreases the mortality of CCl4 intoxicated rats and suppresses the elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) induced by CCl4 in vivo. Also rHSS increases the cell viability and decreases the leakage of intracellular ALT of hepatocytes poisoning by CCl4. The above mentioned results suggest rHSS is an important mechanism for regenerating liver to protect against CCl4 poisoning.

Animals↗
PubMed1988

The cell-surface expression of the cell adhesion molecule cellCAM 105 in rat fetal tissues and regenerating liver.

In the present investigation we have used a sensitive immunohistochemical technique to study the appearance and cell-surface distribution of cellCAM 105 in rat fetal tissues and in regenerating liver. CellCAM 105 is an integral membrane glycoprotein that is involved in cell-cell adhesion of mature rat hepatocytes in vitro. In 12-day-old rat fetuses no cellCAM 105 was detected. CellCAM 105 then appeared on Day 13 in megakaryocytes of the fetal liver, on Day 16 in the liver parenchyme, and on Day 17 in the epithelial cells of the proximal kidney tubules and of the small intestinal mucosa. In the liver parenchyme cellCAM 105 first appeared in immature bile canaliculi. During Days 19-21 a significant staining also occurred on the contiguous sides of the hepatocytes, which at that time became closely associated when the blood-forming cells disappeared. This surface staining then gradually disappeared and 2-3 weeks after birth cellCAM 105 was expressed in the bile canalicular area which is typical of mature hepatocytes. In regenerating liver the amount of cellCAM 105 decreases to a minimum 2-3 days post-hepatectomy, then increases and reaches the normal concentration 10-15 days post-hepatectomy [Odin and Obrink (1986) Exp. Cell Res. 164, 103-114]. The cell-surface distribution of cellCAM 105 also changed, and on Days 3-5 post-hepatectomy it appeared on all faces of the hepatocytes which then were closely associated without obvious sinusoids in between. This staining pattern then slowly changed toward the normal pattern of mature liver, which appeared about 15 days post-hepatectomy. A theoretical analysis of the mode of hepatocyte cell division during liver regeneration suggested that the surface of the postmitotic hepatocytes should become unpolarized with respect to macromolecular composition. This is in agreement with the observed surface distribution of cellCAM 105. The results support the hypothesis that cell-surface interactions mediated by cellCAM 105 might contribute to the regular organization of hepatocytes in the normal, mature liver plates.

Animals↗
PubMed1998

[The sensitivity of carcinogenic initiation effect of regenerated liver induced by diethylnitrosamine in rats].

OBJECTIVE: To compare the sensitivity of carcinogenic initiation effect of regenerated liver with normal liver induced by diethylnitrosamine (DEN) in rats. METHODS: Experimental group was composed of rats that had 2/3 of their liver excised 8 weeks previously, normal rats were used as controls to study: (1) weight of their livers, conventional histological examination and 3H-TdR incorporation test; (2) a modified Solt-Farber carcinogenesis scheme was applied in order to detect the degree of carcinogenic initiation effect by stereologic study of GGT positive preneoplastic liver cell foci; (3) damage of DNA in hepatocytes were detected by in situ nick translation test after DEN treatment both in vivo and in primary cultured liver cells. RESULTS: (1) the regenerative process in liver was completed by the end of the 8th post-operative week and no proliferation of hepatocytes was detected. (2) both the number and volume density of GGT positive foci in the experimental group were higher than those in control group. (3) DNA damage in hepatocytes of experimental group were more severe than in the control group. CONCLUSION: Even after the regeneration process was completed, the regenerated liver still possessed higher sensitivity to carcinogenic initiation effect than normal liver, this sensitivity was related with the severity of DNA damage in hepatocytes of the regenerated liver after DEN attack.

Animals↗
PubMed1981

Epidermal growth factor receptor number decreases during rat liver regeneration.

The potential role of epidermal growth factor (EGF) in the regulation of rat liver regeneration was examined by assessing the binding of 125I-EGF to hepatic membranes isolated at various times after partial hepatectomy. The results demonstrated a fall in 125I-EGF binding detectable as early as 8 h after partial hepatectomy. The nadir in EGF binding, less than 40% of that observed in sham-operated control rats, was seen 36 and 48 h after partial hepatectomy. Scatchard analysis showed that the decrease in binding capacity was due to a fall in receptor number. The specificity of the observed loss of EGF receptors was substantiated in parallel studies of 125I-insulin and 125I-wheat germ lectin binding; the binding of these ligands did not decrease appreciably during liver regeneration. The data are consistent with the hypothesis that EGF or a similar substance is one component of the complex humoral signal that regulates liver regeneration.

Animals↗
PubMed1992

Polyamine plasma levels and liver regeneration following partial hepatic resection in man.

Polyamines (putrescine, spermidine, and spermine) are widely distributed in animal and vegetal tissues, where their intracellular concentration strictly correlates with normal and pathological cell growth and protein synthesis. By means of a sensitive HPLC technique, the fasting plasma concentrations of polyamines were measured serially in 11 patients who underwent partial hepatic resection because of focal liver lesions. Samples were obtained before surgery and over the next 6 months, during hepatic regeneration. Liver volume was also measured by ultrasound on the basis of the 3 maximum diameters of the liver. From 2 to 4 weeks after surgery, plasma putrescine increased by a maximum of 78%, and spermidine by approximately 50%. No changes were observed in spermine levels. The spermidine/spermine ratio nearly doubled during liver regeneration. The volume of the liver decrease from 1505 [SD 236] ml to 743 [151] ml after resection, and returned to nearly normal values after 6 months (1231 [100] ml, p < 0.05 vs. basal values). The liver regeneration rate was highest 2-4 weeks after resection, and declined thereafter, when prevailing polyamine concentrations returned to normal. These data show that liver regeneration is accompanied by a significant increase in fasting putrescine and spermidine concentrations, which might be biochemical signals of active liver cell regeneration.

Adult↗
PubMed2002

Interleukin-6 from intrahepatic cells of bone marrow origin is required for normal murine liver regeneration.

Interleukin-6 (IL-6) is required for normal liver regeneration, but the specific cellular source of this growth factor is unknown. We investigated whether this signal originates from the resident macrophage, the Kupffer cell. Using a murine model of bone marrow transplantation, we replaced recipient bone marrow-derived cells, including Kupffer cells, with cells of donor genetic phenotype. Recipients deficient in IL-6 (IL-6(-/-)) were lethally irradiated, then rescued with 10(7) donor bone marrow cells capable of expressing IL-6 (IL-6(+/+)). Conversely, IL-6(+/+) recipients received IL-6(-/-) marrow. Successful engraftment was measured by the presence of the Y chromosome SRY locus in the livers of female recipients receiving male marrow, in situ IL-6 expression by Kupffer cells, and up-regulation of IL-6 in splenocytes after activation with lipopolysaccharide (LPS). Kupffer cell isolation in IL-6(-/-) females receiving IL-6(+/+) male marrow clearly showed the presence of the SRY locus and IL-6 disrupted allele, whereas males receiving female marrow demonstrated no SRY or IL-6 signals, confirming the extent of replacement. Replacement of these cells in IL-6(-/-) mice with IL-6(+/+) bone marrow successfully restored the regenerative response after partial hepatectomy (PHx) as indicated by signal transduction and activator of transcription 3 (STAT3) activation and hepatocyte DNA replication. Alternatively, complete replacement of Kupffer cells in IL-6(+/+) mice by transplantation with IL-6(-/-) cells significantly inhibited liver regeneration and was partially restored by administration of IL-6. This investigation demonstrates a paracrine mechanism by which cells of bone marrow origin, most likely Kupffer cells, regulate the regenerative capacity of the hepatocyte through IL-6 expression.

Animals↗
PubMedDate not supplied

Evidence that dl-propranolol increases thymidine kinase activity, cell mitosis, and beta-adrenoceptors during rat liver regeneration.

BACKGROUND: Adrenoceptor stimulation has been described as an important factor in liver regeneration. We examined the effects of the beta-adrenoceptor antagonist, dl-propranolol, during early steps of regeneration after partial hepatectomy in rat. METHODS: Thymidine kinase (TK) activity, cell mitosis, and beta-adrenoceptors were measured after a single intraperitoneal (i.p.) injection of dl-propranolol (10 mg/kg) immediately following 70% partial hepatectomy. Enzyme activity was measured as [3H] thymidine (dThd) monophosphate; mitotic index was determined after tissue staining, and beta-adrenoceptors were quantified by saturation binding of [3H] dihydroalprenolol. Liver regeneration was followed for 3 days. RESULTS: dl-Propranolol increased TK activity as early as 12 h postsurgery, after which it leveled off at 24 h and declined at later times; mitotic index increased from 12 to 48 h after injection and beta-adrenoceptors augmented at 24 h compared to partial hepatectomy alone. CONCLUSIONS: dl-Propranolol up-regulated beta-adrenoceptors early after partial hepatectomy with an increase in TK activity and augmented hepatocyte mitosis. These data may suggest that dl-propranolol modulates, probably via beta-adrenoceptor blockade, early steps of liver regeneration.

Adrenergic beta-Antagonists↗
PubMed1991

[Changes of Cu, Zn-SOD and LPO in the regenerating liver after partial hepatectomy--effect of coenzyme Q10 administration].

We have investigated the effect of CoQ10 to lipid peroxide (LPO) and Cu, Zn-SOD in the regenerating liver in rats. Cu, Zn-SOD was investigated in biochemical activity, and immunohistochemical localization. In normal control liver, Cu, Zn-SOD was diffusely stained throughout the hepatic lobules, with predominance in the centrilobular area and with vicinity of thick portal vein. In early stage of regenerating liver. LPO was increased and Cu, Zu-SOD was decreased. Destruction of the membrane of hepatocyte was confirmed by electron microscopy in the early stage of regenerating liver, Cu, Zn-SOD might be speculated to leak out into extra cellular spaces. CoQ10 suppressed the mentioned phenomenon in regenerating liver.

Animals↗
PubMed1998

Putrescine decreases cytochrome P450 3A4 levels during liver regeneration in the rat.

BACKGROUND/AIMS: The mechanism by which many cytochrome P450 (CYP) isozymes decrease during liver regeneration is unclear. Peptides and growth factors are thought to be involved. Putrescine, the first polyamine synthesised by ornithine decarboxylase, peaks early following partial hepatectomy and is known to play an essential role in hepatic regeneration. Gamma amino butyric acid was reported as a physiologic inhibitor of ornithine decarboxylase. In this work we studied the possible involvement of putrescine in the CYP reduction during liver regeneration. METHODS: Hepatectomised, putrescine-treated sham, and GABA-treated hepatectomised rats were used throughout. Total hepatic cytochrome P450, o-dealkylase activities (CYP1A1 and CYP2B1/2), nifedipine oxidase activity (CYP3A4), and Western blot assays of their respective apoproteins were analysed in liver microsomes. Putrescine levels in hepatic tissue were also measured. RESULTS: Partial hepatectomy and putrescine treatment induced a significant diminution in total CYP (50% and 30% of sham-operated rats, respectively). Gamma amino butyric acid treatment prevented this decrease in partially hepatectomised rats. Nifedipine oxidase activity of partially hepatectomised and putrescine-treated rats significantly decreased to 43% and 60% of that in sham-operated rats, respectively. Again, gamma amino butyric acid prevented the diminution in partially hepatectomised rats. No significant changes were observed in o-dealkylase activities. CONCLUSIONS: These results show that inducible CYP1A1 and CYP2B1/2, which are important in carcinogen metabolisation, are preserved after partial hepatectomy. However, constitutive CYP3A4, which represents 50% of total CYP and metabolises drugs like nifedipine, warfarin, acetaminophen, cyclosporin and FK-506, is reduced during liver regeneration. Our experiments suggest that endogenous putrescine is, at least, partly responsible for this decrease.

Animals↗
PubMedDate not supplied

Liver regeneration after living adult right lobe transplantation.

BACKGROUND: The purpose of this study was to describe liver regeneration in patients undergoing living-adult liver transplantation. METHODS: This prospective study included 10 donors and eight recipients who had a total of 65 computed tomographic (CT) scans. All patients had preoperative CT ( n = 18), and follow-up CT scans ( n = 47) were obtained for up to 14 months after transplantation. Liver and spleen volumes were measured by hand tracing each organ on the axial portal venous phase images. RESULTS: Both donors and recipients showed immediate increases in liver volume. However, liver regeneration was significantly faster and reached a higher peak in recipients than in donors. Splenic volume in donors demonstrated an initial increase followed by a decline, reaching the preoperative volume after 1 year. Splenic volume in recipients demonstrated immediate decline postoperatively. CONCLUSION: Restoration of liver volume occurred rapidly after transplantation, but followed different patterns in donors and recipients. Deviation from these patterns warrants further investigation.

Adult↗
PubMed2006

Inhibition of putrescine aminopropyltransferase influences rat liver regeneration.

A close relationship between rat liver regeneration and the concentration ratio of spermidine to spermine (spd:spm) was demonstrated by the oral administration of trans-4-methylcyclohexylamine (MCHA), a specific inhibitor of putrescine aminopropyltransferase. A decrease in recovery rate of remnant liver with MCHA, as a percentage index of remnant liver weight to body weight, correlated well with a decrease of the spd:spm value, with a correlation coefficient of 0.952 for the remnant livers on day 3 after partial hepatectomy. The decrease in recovery rate could be explained by a prolonged cell cycle based on the data of the proliferating cell nuclear antigen labelling index and mitotic cell index in both livers of day 2 and day 3 after partial hepatectomy. The results presented here will give a new aspect in the field of polyamine regulation to control cell growth in vivo.

Animals↗
PubMed1996

Identification of bipotential progenitor cells in human liver regeneration.

Recent studies, including our own, suggest that intermediate filament proteins, particularly bile duct-specific cytokeratin 19 (CK19) and the hepatocyte-specific HepPar1 antigen define the developmental stages of hepatic progenitor cells during liver morphogenesis. We hypothesized that the HepPar1+ CK19+ progenitor cells are activated during human liver regeneration after massive hepatic necrosis and proliferate with the formation of so-called ductular hepatocytes or neocholangioles. We demonstrated previously that the ductular hepatocytes proliferate and share phenotypic characteristics with hepatocytes and biliary epithelial cells. In this investigation, we compared the expression pattern of intermediate filament proteins and HepPar1 antigen in ductular hepatocytes with that of bipotential hepatic progenitor cells. CK14, CK19, vimentin, and HepPar1 antigen were localized by immunoperoxidase staining in 13 human livers with regeneration after massive hepatic necrosis. Double immunostaining of three cases for CK14/CK19 and HepPar1/CK19 was also performed. CK19 reaction exhibited diffuse staining of the cytoplasm of many ductular hepatocytes and bile ducts in all cases. CK14 was expressed in the cytoplasm of ductular hepatocytes and few bile ducts in 5 of 12 specimens. HepPar1 staining was positive in many ductular hepatocytes in 11 of 13 cases. Vimentin was detected in the perinuclear cytoplasm of ductular hepatocytes and some bile duct epithelial cells in all regenerating livers. Double immunostaining for HepPar1/CK19 demonstrated that the ductular hepatocytes contained either HepPar1 or CK19 and that some ductular hepatocytes coexpressed both antigens. CK14, CK19, vimentin, and HepPar1 expression in ductular hepatocytes in human liver regeneration resembles the pattern seen in the developing human liver from 4 to 16 weeks' gestation. This suggests that the ductular hepatocytes recapitulate the developmental stages of bipotential liver progenitor cells and differentiate in steps marked by the acquisition or loss of specific phenotypic characteristics.

Adolescent↗
PubMed1992

Expression and regulation of the cystic fibrosis gene during rat liver regeneration.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) are responsible for cystic fibrosis. The CFTR gene has recently been identified and encodes a 6.5-kb mRNA transcript. Recent observations showing that CFTR expression increases during differentiation of epithelial cells suggested that CFTR may also be regulated in the liver in response to partial hepatectomy (PH). We studied the expression of CFTR in rat regenerating liver and investigated the mechanisms that regulate CFTR RNA levels during a 120-h period after PH. Northern and slot-blot analysis revealed a liver-specific biphasic increase of CFTR mRNA levels, which peaks at 2 and 24 h post-PH. In contrast to these findings, the mode of regulation of the homologous gene MDR-1 showed a clearly different pattern. Nuclear run-on analysis demonstrated increased levels of CFTR transcription corresponding to the time points where an increase in CFTR message was observed. Similarly, the beta-actin gene, which increases transiently during liver regeneration, showed increased nuclear run-on activity 4 h posthepatectomy, indicating that the nuclei were functional. No increase of MDR-1 gene transcription was detected, confirming the previous finding that the increase in MDR-1 mRNA level in regenerating liver results from a post-transcriptional event such as message stabilization. This study indicates that expression of the CFTR gene is regulated during the regenerative process of the liver. The data also suggest that the increase in CFTR and MDR expression levels result from two distinct regulatory mechanisms.

Animals↗