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PubMed2002

Liver regeneration enhanced by orally administered ursodesoxycholic acid is mediated by immunosuppression in partially hepatectomized rats.

The relationship of liver regeneration to immunoactivity was examined after ursodesoxycholic acid (UDCA) administration to partially (about 66%) hepatectomized rats. The UDCA was given orally. Liver regeneration was evaluated by the hepatocyte mitotic index (MI) and immunoactivity by natural killer cell (NK) activity in the blood. When UDCA 12.5 mg/kg/day was administered, a significant increase in the MI was observed 2 and 3 days after hepatectomy, and the MI response 2 days after bepatectomy tended to be dose-dependent in the range of 0-25 mg/kg/day. NK activity was decreased 2 days after hepatectomy when UDCA was given, and a significant correlation between MI and NK activity was obtained. The increase in MI and decrease in NK activity was blocked completely or partially (respectively) by interleukin-2 administration. It was also noted that UDCA did not affect serum parameters indicating liver and kidney function. These findings suggest that liver regeneration can be modified by orally administered UDCA through a change in immunoactivity.

Animals↗
PubMed2005

The hepatoprotective effect of hepatic stimulator substance (HSS) against liver regeneration arrest induced by acute ethanol intoxication.

Male Wistar rats were randomized to receive ethanol (2.5 ml/kg by gastric intubation every 8 hr; group I), equal volumes of isocaloric to ethanol sucrose solution (group II), or ethanol and HSS (100 mg/kg intraperitoneally 10 and 16 hr after partial hepatectomy; groups III and IV, respectively) for up to 96 hr after partial hepatectomy, with ethanol administration starting 1 hr prior to partial hepatectomy. Animals were killed at 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, and 96 hr after partial hepatectomy. The rate of liver regeneration was evaluated by the mitotic index in H&E-stained sections, immunochemical detection of Ki67 nuclear antigen, rate of [3H]thymidine incorporation into hepatic DNA, and liver thymidine kinase enzymatic activity. The biological activity of HSS in groups I and II rats was evaluated using a bioassay. Ethanol administration arrested liver regeneration during the first 32 hr after partial hepatectomy and suppressed HSS activity throughout the period examined. Liver regeneration progressed after 32 hr despite the low levels of HSS activity. HSS administration at 10 and 16 hr reversed liver regeneration arrest induced by ethanol. Acute ethanol administration induces cell cycle arrest during the first 32 hr after partial hepatectomy and suppression of HSS biological activity seems to contribute to this effect. HSS administration reversed the inhibitory effect of ethanol on liver regeneration and caused synchronized entrance of hepatocytes in the S phase of the cell cycle. HSS seems to participate in the network of growth factors controlling the G1/S cell cycle checkpoint.

Acute Disease↗
PubMed2001

A novel role of complement: mice deficient in the fifth component of complement (C5) exhibit impaired liver regeneration.

Components of innate immunity have recently been implicated in the regulation of developmental processes. Most strikingly, complement factors appear to be involved in limb regeneration in certain urodele species. Prompted by these observations and anticipating a conserved role of complement in mammalian regeneration, we have now investigated the involvement of complement component C5 in liver regeneration, using a murine model of CCl(4)-induced liver toxicity and mice genetically deficient in C5. C5-deficient mice showed severely defective liver regeneration and persistent parenchymal necrosis after exposure to CCl(4.) In addition, these mice showed a marked delay in the re-entry of hepatocytes into the cell cycle (S phase) and diminished mitotic activity, as demonstrated, respectively, by the absence of 5-bromo-2'-deoxyuridine incorporation in hepatocytes, and the rare occurrence of mitoses in the liver parenchyma. Reconstitution of C5-deficient mice with murine C5 or C5a significantly restored hepatocyte regeneration after toxic injury. Furthermore, blockade of the C5a receptor (C5aR) abrogated the ability of hepatocytes to proliferate in response to liver injury, providing a mechanism by which C5 exerts its function, and establishing a critical role for C5aR signaling in the early events leading to hepatocyte proliferation. These results support a novel role for C5 in liver regeneration and strongly implicate the complement system as an important immunoregulatory component of hepatic homeostasis.

Animals↗
PubMed2005

The role of prostaglandins in triggering the liver regeneration cascade.

Following injury or surgical resection, the liver has the remarkable ability to regenerate. Despite over 100 years of research, the trigger of the liver regeneration cascade has only recently been identified. Shear stress-induced nitric oxide (NO), released secondary to a hemodynamic event following partial hepatectomy (PHX), has been implicated as the trigger of the liver regeneration cascade. However, it is also known that prostaglandins (PGs) are released following PHX, and in response to shear stress. Therefore, it is hypothesized that PGs, released secondary to an increase in the blood flow-to-liver mass ratio following PHX, trigger the liver regeneration cascade, and that NO and PGs interact during the triggering event. An index of initiation of the liver regeneration cascade, c-fos mRNA expression 15 min after PHX, has been employed. As expected, c-fos mRNA expression increased 15 min after PHX and this increase was inhibited by the NO synthase antagonist, l-NAME. This inhibition was reversed by the NO donors, SIN-1 and SNAP, and by the PGs, PGE2 and PGI2. Also, the increase in c-fos mRNA expression was inhibited by indomethacin, a cyclooxygenase antagonist. This inhibition was also reversed by the NO donors, SIN-1 and SNAP, and by the PGs, PGE2 and PGI2. These results suggest that there is interaction between NO and PGs in triggering the liver regeneration cascade, and that in a situation where either NO or COX is inhibited, provision of excess exogenous NO or PGs can reverse the inhibition. This suggests that exogenous NO and/or PGs may play a role in potentiation of the liver regeneration cascade.

Animals↗
PubMed1993

Inhibition of liver regeneration in mice following extended hepatectomy by transfusion of lymphokine activated killer cells.

Lymphokine activated killer (LAK) cells can destroy not only tumor cells but also syngeneic liver cells. In this study, the effects of passive transfer of LAK cells on liver regeneration were examined by the 3H-thymidine uptake and bromodeoxyuridine (BrdU) labeling methods after resection of 70% of the volume of the liver. LAK cells were infused 12h after hepatectomy and the effects on regeneration of liver cells were examined 36 h later. The transfusion of LAK cells induced significant inhibition of liver regeneration at a dose of 5-10 x 10(7) cells. Neuraminidase treatment of lymphocytes is desirable to enhance the selective entrapment of LAK cells into the liver. When LAK cells were treated with neuraminidase (0.5 units/ml), and transfused into hepatectomized mice, more potent suppression of liver regeneration was induced in comparison with the same dose of LAK cells. The intraperitoneal injection of recombinant interleukin 2 (rIL-2) after partial hepatectomy also inhibited the regeneration of remnant liver. From these results, lymphocytes such as LAK cells appear to regulate liver regeneration.

Animals↗
PubMed1996

Kupffer cell depletion by gadolinium chloride enhances liver regeneration after partial hepatectomy in rats.

Although previous work suggests that tumor necrosis factor-alpha (TNF) promotes liver regeneration after partial hepatectomy (PH), the source of TNF is unknown. If Kupffer cells release TNF after PH, then Kupffer cell depletion by gadolinium chloride (GdCl) should inhibit liver regeneration. To test this hypothesis, cytokine expression and regenerative events were compared in GdCl-treated and control rats. Functional assays and Northern blot analysis of a Kupffer cell-specific mRNA confirmed that GdCl depleted Kupffer cells. Despite this, semiquantitative reverse transcription-polymerase chain reaction analysis of total hepatic RNA showed six- to eightfold higher levels of TNF transcripts in GdCl-treated rats. In this group, PH caused 12-to 16-fold greater induction of interleukin-6, a TNF-inducible cytokine, and two- to threefold greater induction of several cytokine-regulated genes (c-jun, C/EBP-beta, and C/EBP-delta). GdCl also amplified regeneration-associated increases in the DNA binding activity of AP-1, a growth regulatory transcription factor. Furthermore, hepatic incorporation of [3H]thymidine, expression of the S-phase antigen, proliferating cell nuclear antigen, and the hepatocyte mitotic index were each significantly greater in GdCl-treated rats. Thus, although GdCl causes Kupffer cell depletion, it does not decrease liver TNF and actually enhances liver regeneration after PH.

Animals↗
PubMed2005

Transient changes in the expression pattern of key enzymes for bile acid synthesis during rat liver regeneration.

Changes in the expression patterns of genes involved in bile acid (BA) synthesis were investigated during rat liver regeneration that follows two-thirds partial hepatectomy. BAs in bile were measured by GC-MS and the absolute and relative abundance of specific mRNAs in the liver by RT-real-time quantitative PCR. Cyclin E mRNA, used as an indicator of liver cell proliferation, peaked at day 1. The levels of mRNA of alpha-fetoprotein transcription factor (FTF) and small heterodimer partner (SHP) were first reduced (day 1) and then (days 2-3) increased, when those of farnesoid X receptor (FXR) were also transiently enhanced. The early (day 1) up-regulation of Cyp7a1, and Cyp8b1, together with the down-regulation of Cyp27, was consistent with an increased proportion of cholic acid versus chenodeoxycholic acid and a progressive recovery in total BAs secretion. The transient appearance of flat BAs (allo-BAs plus Delta4-unsaturated-BAs) during rat liver regeneration was probably due to the changes in the expression ratio of steroid 5alpha- versus 5beta-reductase. Both were first (day 1) down-regulated and then up-regulated (5alpha-reductase more than 5beta-reductase). In conclusion, changes in the expression patterns of nuclear receptors and enzymes involved in BA synthesis are consistent with the transient modifications that occur in BA pool during rat liver regeneration.

Animals↗
PubMed2001

Evaluation of liver regeneration using the L-[1-13C]methionine breath test.

BACKGROUND: We examined the relationship between changes in the liver weight/body weight percentage, amount of hepatic tissue total DNA, and the results of the [1-(13)C]methionine ((13)Cmet) breath test during hepatic regeneration in a rat model of 70% hepatectomy, to assess their usefulness for evaluating hepatic regeneration. MATERIALS AND METHODS: Male Wistar rats (230-290 g) were subjected to 70% hepatectomy under anesthesia with Nembutal. One, 2, 3, 7, and 14 days postoperatively, 40 mg/kg (13)Cmet was intravenously injected into the femoral vein, and the increase in exhaled (13)CO(2) (Delta(13)CO(2)) was measured for 15 min. Simple laparotomy was performed in control rats. Following the breath test, the regenerated liver was removed and weighed. The amount of DNA was determined. RESULTS: The correlation coefficients (r) between liver weight/body weight (LW/BW) and results of the (13)Cmet breath test, and between DNA and results of the (13)Cmet breath test were 0.892 and 0.800, respectively. CONCLUSIONS: The (13)Cmet breath test is considered to be very useful for assessing liver regeneration, and total (13)CO(2) output over 15 min in the (13)Cmet breath test graph seems to be an effective indicator for evaluating liver regeneration.

Animals↗
PubMed1996

Review: regulation of liver regeneration by pro-inflammatory cytokines.

The liver has tremendous regenerative capacity. This distinguishes it from other vital organs (e.g. the brain, heart and lungs) that cannot replace functional tissue once it has been destroyed. Although hepatocytes rarely proliferate in the healthy adult liver, virtually all surviving hepatocytes replicate at least once after 70% partial hepatectomy. Therefore, partial liver resection has been used to characterize mechanisms that regulate liver regeneration. Residual hepatocytes up-regulate both proliferative and liver-specific gene expression in order to preserve tissue specific function. In addition, hepatocyte proliferation is tightly co-ordinated to complement regenerative responses in hepatic non-parenchymal cells (e.g. endothelia, biliary epithelia, stellate and Kupffer cells), so that the entire organ can be reconstituted within days. Studies with neutralizing antibodies to tumour necrosis factor-alpha (TNF) clearly demonstrate that, after partial hepatectomy, TNF promotes liver cell proliferation. The present review focuses on the regulation of the hepatocyte proliferative response by pro-inflammatory cytokines.

Cell Division↗
PubMed2004

Delayed hepatocellular mitotic progression and impaired liver regeneration in early growth response-1-deficient mice.

The early growth response-1 transcription factor (Egr-1) is induced as part of the immediate-early gene expression response during early liver regeneration. In the studies reported here the functional significance of EGR-1 expression during liver regeneration was examined by characterizing the hepatic regenerative response to partial hepatectomy in Egr-1 null mice. The results of these studies showed that liver regeneration in Egr-1 null mice is impaired. Although activation of interleukin-6-STAT3 signaling, regulation of expression of hepatic C/ebpalpha, C/ebpbeta, cyclin D, and cyclin E and progression through the first wave of hepatocellular DNA synthesis occurred appropriately following partial hepatectomy in Egr-1 null mice, subsequent signaling events and cell cycle progression after the first round of DNA synthesis were deranged. This derangement was characterized by increased activation of the p38 mitogen-activated protein kinase and inhibition of hepatocellular metaphase-to-anaphase mitotic progression. Together these observations suggest that EGR-1 is an important regulator of hepatocellular mitotic progression. In support of this, microarray-based gene expression analysis showed that induction of expression of the cell division cycle 20 gene (Cdc20), a key regulator of the mitotic anaphase-promoting complex, is significantly reduced in Egr-1 null mice. Taken together these data define a novel functional role for EGR-1 in regulating hepatocellular mitotic progression through the spindle assembly checkpoint during liver regeneration.

Anaphase↗
PubMed2002

[Liver regeneration after partial hepatectomy. Role of lipid mediators].

The paper contains current data on the different ways of the liver regeneration. There is still not enough data about control of the regeneration processes in the liver. However nuclear phosphatidylinositols and sphingomyelins have been shown to play a potent role of messengers signaling. The lipid messengers may be potent factors affecting process of liver regeneration after partial hepatectomy.

Animals↗
PubMed1986

Sequential protooncogene expression during rat liver regeneration.

When growth is stimulated in the normally quiescent adult rat liver by partial hepatectomy, steady state levels of messenger RNAs (mRNAs) for c-fos, c-myc, and p53 increase sequentially during the prereplicative phase which precedes DNA synthesis. Levels of c-fos mRNA are elevated at least 4-fold within 15 min after partial hepatectomy and decrease rapidly by 2 h; c-myc mRNA reaches maximal levels (5-fold over normal) between 30 min and 2 h after the operation. A second, transient phase of expression for both c-fos and c-myc occurs around 8 h after partial hepatectomy. p53 mRNA levels increase between 8 and 12 h after the operation (5-fold over normal) and are reflected in an elevation of steady state levels of p53 protein between 12 and 15 h after partial hepatectomy. The levels of ras p21 protein increase much later at a time of active DNA replication and cell division. Actinomycin D injected at the time of partial hepatectomy blocks the increase in c-myc at 2 h but has no effect on c-fos mRNA levels. Actinomycin D injected at 6 h only partially blocks the increase in c-myc and p53 mRNA at 8 h but does not affect c-fos mRNA. Our results suggest that the transient and sequential expression of protooncogenes during the prereplicative stage of liver regeneration is likely to reflect events associated with entry and progression of hepatocytes into the cell cycle and can serve as markers for identifying specific humoral factors involved in liver regeneration.

Albumins↗
PubMed1997

Detection of a tyrosine-phosphorylated form of cyclin A during liver regeneration.

Cyclin A functions in both the S and G2-M phases of the cell cycle. The expression of cyclin A during liver regeneration was compared with that of cyclin B1 and p34cdc2. Liver regeneration was followed at 2-h intervals from 12 to 48 h after partial hepatectomy (PH). Immunohistochemical staining using proliferating cell nuclear antigen revealed DNA synthesis peaks at 18 h after PH. The most intense nuclear staining of hepatocytes with cyclins A and B1 and p34cdc2 antibodies occurred at 26 h post-PH, which corresponds with the onset of mitosis. Quantitative mRNA expression of cyclins A and B1 and p34cdc2 was determined by competitive reverse transcription-PCR. Construction of mRNA internal standards and coamplification during reverse transcription-PCR allowed quantitation of all three cell cycle genes. At 24 h post-PH, cyclin A mRNA levels were approximately 5 fg/100 ng total RNA. In contrast, cyclin B1 and p34cdc2 levels were 20-fold higher, 100 fg/100 ng total RNA. Cyclin B1 and p34cdc2 mRNA levels showed two peaks, at 26 and 38-44 h post-PH, whereas the levels of cyclin A were constant during this interval. Immunoblots revealed the presence of cyclin A in normal liver, and significant amounts were present as early as 12 h post-PH. At 26 h post-PH, tyrosine-phosphorylated forms of cyclin A were detected. Cyclin B1 and p34cdc2 protein were not present until 22-24 h post-PH, and two peaks were observed, at 26 and 38-44 h, coinciding with the mRNA pattern. Histone H1 kinase activity was associated with the two peaks of cyclin B1 and p34cdc2 expression. The unique pattern of cyclin A expression and detection of tyrosine-phosphorylated forms suggest a different mechanism for the regulation of cyclin A during liver regeneration.

Animals↗
PubMed1981

The appearance of new polyadenylated nuclear RNA sequences during rat-liver regeneration.

Polyadenylated RNA populations from normal and 16-hour regenerating rat-liver nuclei were compared by heterologous hybridisation reactions with cDNA and unique DNA probes. Whereas unique DNA hybridisations did not show differences between the RNA populations, comparisons by cDNA hybridisation showed that about 10--15% by weight of polyadenylated sequences present in the nuclei of 16-hour regenerating rat livers were not found in the polyadenylated nuclear RNA of normal rat livers. These regenerating-specific nuclear cDNA sequences were isolated and characterised; the experiments showed that the complexity of the new sequences was 1-2 x 10(7) nucleotides (equivalent to 5,000--10,000 RNA sequences of 2,000 nucleotides in length) and that they were probably not potential messenger RNA sequences.

Animals↗
PubMed1981

Modulation of nuclear protein kinase activity and phosphorylation of histone H1 subspecies during the prereplicative phase of rat liver regeneration.

We have measured nuclear protein kinase activity during the prereplicative phase of rat liver regeneration. Total nuclear protein kinase activity increased significantly 15-18 h after partial hepatectomy, with the peak of activity occurring at 16 h. DEAE-Sephacel chromatography resolved nuclear protein kinase activity into two cAMP-independent (Ib and II) and two cAMP-dependent (Ia and III) protein kinases. Sixteen h after partial hepatectomy, there was a marked increase in the activities of the nuclear cAMP-dependent protein kinases and a decrease in the activity of nuclear cAMP-independent protein kinase II. Characterization of the two nuclear cAMP-dependent protein kinases revealed them to be identical with the cytosolic type I and II isozymes. Immunotitration of nuclear catalytic subunit and densitometric analysis of autoradiographs from 8-azido-[32P]cAMP-labeled nuclear RI revealed increases in both subunits 16 h afer partial hepatectomy. Concomitantly with the observed increase in nuclear protein kinase activity, we have observed an increase in the phosphorylation of histone H1 subspecies. Administration of the beta-adrenergic antagonist DL-propranolol, which has been shown to cause delays of equal duration in both the second phase of increased intracellular cAMP levels and the initiation of DNA synthesis (MacManus, J. P., Braceland, B. M., Youdale, T., and Whitfield, J. F. (1973) J. Cell. Physiol. 82, 157-164), results in an equivalent delay of increased nuclear protein kinase activity. Colchicine, which has previously been shown to prevent the onset of DNA synthesis (Walker, P. R., and Whitfield, J. F. (1978) Proc. Natl. Acad. Sci. U. S. A. 75, 1394-1398), also prevents the increased protein kinase activity normally observed 16 h after partial hepatectomy. We conclude that the onset of DNA synthesis in the regenerating rat liver is preceded by a cAMP-mediated translocation of type I and type II cAMP-dependent protein kinase to the nucleus and phosphorylative modification of histone H1 subspecies. The inhibitory effects of propranolol and colchicine suggest a common cAMP-mediated, colchicine-sensitive link between protein kinase translocation and the initiation of DNA synthesis.

Animals↗
PubMed2006

A molecular view of liver regeneration.

The purpose of this review was to carry out an analysis of the liver regenerative process focusing on the molecular interactions involved in this process. The authors undertook a review of scientific publications with a focus on the liver regeneration. The cellular processes involved in liver regeneration require multiple systematic actions related to cytokines and growth factors. These interactions result in the initiation of mitogenic potential of the hepatocytes. The action of these modulators in the regenerative process require a processing in the extra-cellular matrix. Serines and metal proteins are responsible for the bio availability of cytokines and growth factors so that they can interact as receptors in the cellular membrane generating signaling events for the beginning and end of the liver regenerative process. The exact mechanism of interaction between cells, cytokines and growth factors is not well established yet. A series of ordered events that result in the hepatic tissue regeneration has been described. The better understanding of these interactions should provide a new approach of the treatment for liver diseases, aiming at inducing the regenerative process.

Cell Proliferation↗