Treatment with a novel lipid A analogue, FS-112, and partial hepatectomy causes submassive liver necrosis and impaired liver regeneration in mice

A novel experimental model of submassive liver necrosis with impaired regeneration has been established. A novel lipid A analogue, FS-112, was injected intravenously into male BALB/c mice, followed 2 days later by a 70% partial hepatectomy. Over the next 9 days, mice became severely jaundiced, with a peak total bilirubin (TBil) concentration of (mean±s.d.) 12.9±2.1 mg/dL 7 days postoperatively. In contrast, the TBil concentration in vehicle-treated mice remained less than 2 mg/dL. Significant elevations of L-alanine:2-oxoglutarate aminotransferase (ALT) were also observed 3–7 days after the operation in mice pretreated with FS-112, compared with mice pretreated with the vehicle. Submassive liver necrosis was observed with extensive mononuclear cell infiltration in mice treated with FS-112 and subjected to partial hepatectomy. Furthermore, both the BrdU and the proliferating cell nuclear antigen (PCNA) labelling index (LI) 1 day following partial hepatectomy in mice pretreated with FS-112 (8.6±4.3 and 7.9±4.2%, respectively) were significantly lower than levels in vehicletreated mice (25.8±3.8 and 26.5±10.5%, respectively). The time course of changes in the BrdU LI in liver specimens from mice treated with both FS-112 and partial hepatectomy did not increase, even 3, 5, and 7 days postoperatively. Excellent liver regeneration with a PCNA LI 10-fold higher than the resting level was observed in mice treated with D-galactosamine hydrochloride. These results strongly suggest that this animal model of submassive liver necrosis may be suitable for clarifying the mechanisms of impaired liver cell regeneration often seen in fulminant hepatitis.     

Role of angiotensin‐1 receptor blockade in cirrhotic liver resection

Background: The regeneration capacity of cirrhotic livers might be affected by angiotensin‐1 (AT1) receptors located on hepatic stellate cells (HSC). The effect of AT1 receptor blockade on microcirculation, fibrosis and liver regeneration was investigated. Materials and methods: In 112 Lewis rats, cirrhosis was induced by repetitive intraperitoneal injections of CCl₄. Six hours, 3, 7 and 14 days after partial hepatectomy or sham operation, rats were sacrificed for analysis. Animals were treated with either vehicle or 5 mg/kg body weight losartan pre‐operatively and once daily after surgery by gavage. Microcirculation and portal vein flow were investigated at 6 h. The degree of cirrhosis was assessed by Azan Heidenhein staining, activation of HSC by desmin staining, apoptosis by ssDNA detection and liver regeneration by Ki‐67 staining. Changes in expression of various genes important for liver regeneration and fibrosis were analysed at 6 h and 3 days. Haemodynamic parameters and liver enzymes were monitored. Results: Losartan treatment increased sinusoidal diameter, sinusoidal blood flow and portal vein flow after partial hepatectomy (P<0.05), but not after sham operation. AT1 receptor blockade resulted in increased apoptosis early after resection. HSC activation was reduced and after 7 days, a significantly lower degree of cirrhosis in resected animals was observed. Losartan increased the proliferation of hepatocytes at late time‐points and of non‐parenchymal cells early after partial hepatectomy (P<0.05). Tumour necrosis factor (TNF)‐α was significantly upregulated at 6 h and stem cell growth factor (SCF) was downregulated at 3 days (P<0.05). Conclusion: Losartan increased hepatic blood flow, reduced HSC activation and liver fibrosis, but interfered with hepatocyte proliferation after partial hepatectomy in cirrhotic livers.     

Comparative study of the effects of terlipressin versus splenectomy on liver regeneration after partial hepatectomy in rats

BACKGROUND: Post-hepatectomy liver failure as a result of insufficient liver remnant is a feared complication in liver surgery. Efforts have been made to find new strategies to support liver regeneration. The aim of this study was to investigate the effects of terlipressin versus splenectomy on postoperative liver function and liver regeneration in rats undergoing 70%partial hepatectomy. METHODS: Seventy-two male Wistar rats were randomly assigned into three groups(n=24 in each group): 70% partial hepatectomy as control(PHC), 70% partial hepatectomy with splenectomy(PHS) or 70% partial hepatectomy with a micropump for terlipressin administration(PHT). Eight rats in each group were sacrificed on postoperative day(POD) 1,3 and 7. To assess liver regeneration, immunohistochemical analysis of liver tissue using bromodeoxyuridine(BrdU) and Ki-67 labeling was performed. Portal venous pressure, serum concentrations of creatinine, urea, albumin, bilirubin and prothrombin time as well as liver-, body-weight and their ratio were determined on POD 1, 3 and 7.RESULTS: The liver-, body-weight and their ratio were not statistically different among the groups. On POD 1, 3 and 7 portal venous pressure in the intervention groups(PHT:8.13 ±1.55, 10.38±1.30, 6.25±0.89 cm H_2O and PHS: 7.50±0.93,8.88 ±2.42, 5.75±1.04 cm H_2O) was lower compared to the control group(PHC: 8.63±2.06, 10.50±2.45, 6.50±2.67 cmH_2O). Hepatocyte proliferation in the intervention groups was delayed, especially after splenectomy on POD 1(Brd U: PHS vs PHC, 20.85% ±13.05% vs 28.11%±10.10%; Ki-67, 20.14%±14.10% vs 23.96% ±11.69%). However, none of the differences were statistically significant.CONCLUSIONS: Neither the administration of terlipressin nor splenectomy improved liver regeneration after 70% partial hepatectomy in rats. Further studies assessing the regulation of portal venous pressure as well as extended hepatectomy animal models and liver function tests will help to further investigate mechanisms of liver regeneration.     

Role of the oestrogen receptor in liver regeneration in the male rat

Partial hepatectomy in male rats results in raised serum oestrogen levels, nuclear binding of oestrogen receptor (ER) and feminization of certain aspects of hepatic metabolism. It has been proposed that these changes may have an important role in liver regeneration. The present study was performed to ascertain the effects of the oestrogen agonist diethylstilbestrol (DES), 2 mg/kg, and the oestrogen antagonist tamoxifen (TAM), 2 mg/kg, on liver regeneration induced by partial hepatectomy in the male rat. Regenerative activity was determined by incorporation of [³H]-thymidine into hepatic DNA as well as by measurement of liver remnant weight. Following partial hepatectomy, there was a trend towards an increase in liver remnant weight at 24 h in rats treated with DES (DES, 5.95 ± 1.52 g; vehicle, 4.87 ± 0.66 g; P= 0.06) though by 48 h no effect was found. Tamoxifen treatment did not significantly affect liver weight at 24 h but by 48 h there was a highly significant reduction in liver remnant weight (TAM, 5.41 ± 0.85 g; vehicle, 7.31 ± 1.43 g; P < 0.001). Neither DES nor TAM treatment influenced liver regeneration as determined by [³H]-thymidine incorporation into hepatic DNA. We conclude that pharmacologic manipulation of oestrogens does not influence the initiation of the regenerative process but that oestrogen may facilitate later phases of hepatic growth.     

Proliferating cell nuclear antigen (PCNA) expression in regenerating rat liver after partial hepatectomy

Proliferating cell nuclear antigen (PCNA) is a nuclear protein maximally elevated in the S phase of proliferating and transformed cells and is recognized by the monoclonal antibody PC-10 in paraffin tissue sections. The liver regenerative process after partial hepatectomy in rats was estimated with thein vivo incorporation of [³H]thymidine into liver DNA and the liver thymidine kinase activity. The expression of PCNA in rat liver after partial hepatectomy was performed by immunohistochemical staining with PC-10 in paraffin embedded tissues, at different time intervals up to 240 hr. Proliferating cell nuclear antigen expression, [³H]thymidine incorporation into DNA, and liver thymidine kinase activity exhibited marked oscillations during the liver regenerative process. A close relationship was demonstrated among DNA synthesis, thymidine kinase activity, and PC-10 score. Our results suggest that PC-10 monoclonal antibody may be used as a worthwhile proliferation index in the evaluation of the rate of liver regeneration in rats.     

Hepatocyte and Kupffer cell function after liver transplantation in the rat –in vivo evaluation with dynamic scintigraphy

Abstract: In vivo physiological measurements of hepatocyte and Kupffer cell function after liver transplantation are desirable. Orthotopic liver transplantation was performed in 54 rats. Hepatocyte and Kupffer cell function were measured with dynamic liver scintigraphy. Hepatic clearance of ^99mTc-Nanocoll (%/min), an albumin colloid phagocytosed by the Kupffer cells, was used to evaluate Kupffer cell function. Hepatic clearance of ^99mTc-IODIDA (%/min), an imino-diacetic-acid taken up and secreted by the hepatocytes, was used to evaluate the hepatocyte function. Hepatic clearance in control rats was 27±2 %/min for Nanocoll and 30±3 %/min for IODIDA. After syngenic liver transplantation, without rejection, there was a rise in Nanocoll clearance (34±2 %/min p<0.01) after 3 weeks, but no change in IODIDA clearance (32±3 %/min N.S.). After syngenic liver transplantation with preservation time prolonged to 16 h, there were no changes in IODIDA or Nanocoll clearance 1 day after transplantation. Both IODIDA (11±2 %/min) and Nanocoll clearance (22±2 %/min) were decreased (p<0.001) during rejection after allogenic transplantation. An in vivo method of measuring the hepatocyte and Kupffer cell function in the transplanted liver is described. Kupffer cell function was increased after syngenic liver transplantation. Kupffer cell and hepatocyte function were decreased during rejection. Dynamic liver scintigraphy seems a suitable procedure for examining liver injury after liver transplantation in the experimental setting.     

5-HT及其受体在大鼠肝再生过程中的作用

目的分析5-羟色胺（5-HT）及其受体在大鼠肝脏再生过程中的作用。方法将50只雄性Wistar大鼠随机分成实验组和对照组。实验组大鼠于肝大部分切除术后24、36、48和72h处死,对照组行假手术。采用流式细胞技术检测大鼠肝脏增殖细胞核抗原（PCNA）表达、免疫组化法检测Ki67及5-HT表达、实时荧光定量PCR检测5-HT2A、2B受体亚型的表达。结果肝大部切除术后大鼠肝脏重量逐渐增加,PCNA和Ki67表达于术后24和36h达高峰;在肝切除术后各个时间点5-HT2A、2B受体在肝脏中的表达均显著升高,以术后36h最高;术后36h空肠嗜铬细胞5-HT含量高于24h,且都高于正常大鼠。结论肝脏再生过程中5-HT合成及其受体表达均显著上调,可能与肝脏的再生有关。     

Erythropoietin promotes hepatic regeneration after extended liver resection in rats

Background and Aim:  It has been proven in various animal studies that recombinant human erythropoietin (rHuEPO) protects renal, cardiac and neuronal, as well as hepatic, tissue from ischemia, and promotes regeneration of adult central nervous system neurons. To date, no data are available as to whether rHuEPO has the ability to stimulate liver regeneration after liver resection.
Methods:  Rats undergoing 70% or 90% hepatectomy received an intraportalvenous administration (i.p.) of rHuEPO prior to resection or a subcutaneous injection (s.c.) for 3 days postoperatively, control animals were treated with surgery and saline injection only. Regeneration capacity of remnant livers was studied over 7 days by histology and immunohistochemistry (Ki-67, proliferating cell nuclear antigen [PCNA]). Polymerase chain reaction was carried out to measure transforming growth factor β (TGF-β), hypoxia induced factor (HIF), signal transducing activator 3 and vascular endothelial growth factor.
Results:  Ten-day survival in rats undergoing 90% hepatectomy significantly increased in i.p.-pretreated animals. After 70% hepatectomy the mitotic index was significantly increased in both rHuEPO-treated groups. These data were confirmed by PCNA and Ki-67 expression, which was significantly increased in the treated groups 24 h and 2 days after liver resection. TGF-β and HIF mRNA both were upregulated in control animals 3 h after surgery.
Conclusion:  rHuEPO effectively increased liver regeneration in rats after 70% liver resection and enhanced survival after 90% hepatectomy. Thus, rHuEPO may increase the regenerative capacity after major hepatectomy.     

Mechanism of impaired regeneration of fatty liver in mouse partial hepatectomy model

BACKGROUND AND AIM: The mechanism of injury in steatotic liver under pathological conditions been extensively examined. However, the mechanism of an impaired regeneration is still not well understood. The aim of this study was to analyze the mechanism of impaired regeneration of steatotic liver after partial hepatectomy (PH). METHODS: db/db fatty mice and lean littermates were used for the experiments. Following 70% PH, the survival rate and recovery of liver mass were examined. Liver tissue was histologically examined and analyzed by western blotting and RT-PCR. RESULTS: Of 35 db/db mice, 25 died within 48 h of PH, while all of the control mice survived. Liver regeneration of surviving db/db mice was largely impaired. In db/db mice, mitosis of hepatocytes after PH was disturbed, even though proliferating cell nuclear antigen (PCNA) expression (G1 to S phase marker) in hepatocytes was equally observed in both mice groups. Interestingly, phosphorylation of Cdc2 in db/db mice was suppressed by reduced expression of Wee1 and Myt1, which phosphorylate Cdc2 in S to G2 phase. CONCLUSIONS: In steatotic liver, cell-cycle-related proliferative disorders occurred at mid-S phase after PCNA expression. Reduced expression of Wee1 and Myt1 kinases may therefore maintain Cdc2 in an unphosphorylated state and block cell cycle progression in mid-S phase. These kinases may be critical factors involved in the impaired liver regeneration in fatty liver.     

Extent of right hepatectomy determines postoperative donor albumin and bilirubin changes: new insights

Background: Changes in donor plasma albumin (Alb) and bilirubin (Tbili) are common following right hepatectomy for liver transplantation. We conducted a retrospective study to determine whether the size of the liver resection and the estimated blood loss (EBL) impact these laboratory values in the first week (early) and third week (late) postoperatively. Methods: Demographics and peri‐operative data of 34 donors undergoing right hepatectomy were analysed by Spearman's correlation (data in means±SD, P<0.05=statistically significant). Re‐admissions for pleural effusions were tracked. Results: Donors were 26–56 (43.3±9.1) years old, body mass index (kg/m²) was 27.7±4.2, liver resected (%) was 58±7 and EBL (mL) was 1505±927. A larger hepatectomy correlated with lower Alb at 3 weeks (P=0.03) and also with a higher early (P=0.025) and late Tbili (P=0.037). Larger blood loss determined low Alb in the first week (P=0.013), still noticeable 3 weeks postoperatively (P=0.047). Re‐admissions for pleural effusion were not associated with the size of the liver resection or postoperative Alb changes. Conclusions: A remaining liver size‐dependent reduced synthetic hepatic function may explain the persistent low Alb that becomes apparent at end of the preoperative Albs half‐life. A size‐related diminished metabolic liver capacity results in early and late elevated Tbili. Prospective studies are needed to better understand the impact of resection size on hepatic physiology, donor care and clinical outcomes.     

Multivariate analysis of liver regenerative capacity after hepatectomy in humans

Many factors affect liver regeneration after partial hepatectomy; however, those factors that are essential for regulation of liver regeneration in humans are not known. Using multiple regression analysis we conducted a study to determine essential factors involved in the speed of liver regeneration after hepatectomy. The subjects were 59 patients who underwent hepatic resection between January 1980 and December 1991. A regression equation for predicting regeneration speed (Y; cm³/day) during the 1st postoperative month was obtained by stepwise forward multiple regression analysis, using 11 explanatory parameters (Xi). The regeneration speed and the resection ratio (%; indicating the magnitude of resection) were calculated based on a computed tomography (CT) scan volumetric study. The degree of liver fibrosis, expressed as the fibrotic index (%), was morphometrically determined in Azan-Mallory stained sections. Of the 11 explanatory parameters, the resection ratio and the fibrotic index had a significant simple correlation with Y. The following regression equation was obtained: Y (cm³/day)=?1.1+3.7 × resection ratio ?5.4 × alkaline phosphatase ?3.7 × fibrotic index +1.2 × total bilirubin ?2.6 × glutamic pyruvic transaminase (multiple correlation coefficient, 0.82). We found that the extent of resection and the degree of fibrosis, as well as alkaline phosphatase, total bilirubin, and glutamic pyruvic transaminase, contributed to the speed of regeneration after partial hepatectomy.     

Differential regenerative response and expression of growth factors following hepatectomy of variable extent in rats

Abstract: Aims/Background: Liver regeneration is a physiological mechanism which leads to restoration of the hepatic parenchyma following hepatectomy or toxic injury. This process is mediated by a wide variety of cytokines and growth factors. The aim of the present study was to evaluate the influence of hepatectomy extent on the levels of intrahepatic mRNAs for cell-cycle markers and growth factors in rats submitted to a 30%, two-third or 80% hepatectomy. Methods: Cyclins, thymidine kinase and growth factors mRNA levels were quantitatively assessed by RT-PCR at different time points post-hepatectomy (2h, 6h, 12h, days 1, 2, 6). Results: As compared with a two-third hepatectomy, cyclins and thymidine kinase mRNA levels were increased but with a delayed peak at day 2 in the 80% hepatectomy group and showed a progressive increase until day 6 in the 30% hepatectomy group; mRNA levels for HGF or TGFα were increased with a delayed peak at 12 h or day 2 in the 80% hepatectomy group, respectively and this delay was more pronounced in the 30% hepatectomy group with a peak at day 1 or day 6. Conclusion: A regenerative response occurs whatever the extent of hepatectomy but the course of regeneration and expression of growth factors differs according to the volume of resected liver. A better knowledge of these events could improve the clinical results of hepatic resection for primary or metastatic liver disease.     

The effect of ursodeoxycholic acid on liver regeneration after partial hepatectomy in rats with non-alcoholic fatty liver disease

Aim:  To investigate the effect of ursodeoxycholic acid (UDCA) on liver regeneration following partial hepatectomy in rats with non-alcoholic fatty liver disease (NAFLD).
Methods:  UDCA was administered to seven rats (group 1) and physiological saline was administered both to seven rats (group 2) with NAFLD and to seven rats with normal livers (group 3). All rats underwent two-thirds hepatectomy and the remnant liver tissues were removed 48 h later. Mitotic index (MI) and levels of proliferating cell nuclear antigen (PCNA), glutathione (GSH) and malondialdehyde (MDA) were assayed.
Results:  MI and PCNA levels in group 2 were significantly lower than in groups 1 and 3, but the values in groups 1 and 3 were similar. The GSH levels of group 2 were significantly lower than those of group 3 in the hepatectomy tissues, and lower than those of groups 1 and 3 in the remnant tissues. The differences between GSH levels in groups 1 and 3 were not significant. MDA levels in hepatectomy and remnant tissues were significantly higher in group 2 compared to groups 1 and 3; values in groups 1 and 3 were similar.
Conclusion:  UDCA increases regeneration after partial hepatectomy in rats with NAFLD, possibly due to an attenuating effect on oxidative stress.     

Endothelial autophagy is not required for liver regeneration after partial hepatectomy in mice with fatty liver

Background & Aims

Patients with non-alcoholic fatty liver disease (NAFLD) have impaired liver regeneration. Liver endothelial cells play a key role in liver regeneration. In non-alcoholic steatohepatitis (NASH), liver endothelial cells display a defect in autophagy, contributing to NASH progression. We aimed to determine the role of endothelial autophagy in liver regeneration following liver resection in NAFLD.

Methods

First, we assessed autophagy in primary endothelial cells from wild type mice fed a high fat diet and subjected to partial hepatectomy. Then, we assessed liver regeneration after partial hepatectomy in mice deficient (Atg5^lox/lox;VE-cadherin-Cre⁺) or not (Atg5^lox/lox) in endothelial autophagy and fed a high fat diet. The role of endothelial autophagy in liver regeneration was also assessed in ApoE^−/− hypercholesterolemic mice and in mice with NASH induced by methionine- and choline-deficient diet.

Results

First, autophagy (LC3II/protein) was strongly increased in liver endothelial cells following hepatectomy. Then, we observed at 40 and 48 h and at 7 days after partial hepatectomy, that Atg5^lox/lox;VE-cadherin-Cre⁺ mice fed a high fat diet had similar liver weight, plasma AST, ALT and albumin concentration, and liver protein expression of proliferation (PCNA), cell-cycle (Cyclin D1, BrdU incorporation, phospho-Histone H3) and apoptosis markers (cleaved Caspase-3) as Atg5^lox/lox mice fed a high fat diet. Same results were obtained in ApoE^−/− and methionine- and choline-deficient diet fed mice, 40 h after hepatectomy.

Conclusion

These results demonstrate that the defect in endothelial autophagy occurring in NASH does not account for the impaired liver regeneration occurring in this setting.     

Beneficial Effects of Fluvastatin on Liver Microcirculation and Regeneration After Massive Hepatectomy in Rats

Fluvastatin, the first entirely synthetic statin, has a significant cholesterol-lowing effect comparable with other statins. In addition, it has been shown to inhibit oxidative stress and improve vascular endothelial function. The aim of this study was to clarify the pretreatment effects of fluvastatin on liver function after massive hepatectomy in rats. Six-week-old male Wister rats were divided into two groups: a fluvastatin group (group F), pretreated with oral administration of fluvastatin (20 mg/kg per day) for 2 days before 90% hepatectomy; and a control group (group C), pretreated with vehicle for 2 days before hepatectomy. Animals were sacrificed at 0, 12, 24, 48, and 72 h after hepatectomy. The liver regeneration rate, liver function tests, and hepatic stellate cell activation were examined. The liver regeneration rate in group F was significantly higher at 72 h after hepatectomy (P < 0.05). The serum level of total bilirubin in group F was significantly lower at 48 h after hepatectomy (P < 0.05). Sinusoidal area in group F was maintained histologically. Furthermore, the expression of alpha smooth-muscle actin (α-SMA) protein in the liver was inhibited in group F at 48 h after hepatectomy. This study demonstrated the beneficial effects of fluvastatin in a lethal massive hepatectomy model using rats, with improved hepatic regeneration and microcirculations, by inhibiting the activation of hepatic stellate cells.     

Failure of regeneration of the steatotic rat liver: disruption at two different levels in the regeneration pathway

Hepatic resection or transplantation in patients with fatty liver is associated with increased morbidity and mortality. The regenerative capacity of fatty livers after major tissue loss is unknown. Interleukin 6 (IL-6) is a potent inducer of hepatic regeneration in normal and ischemic livers. Therefore, we studied hepatic regeneration at day 1, day 2, and day 4 in a model of 70% hepatectomy in obese and lean Zucker rats, and obese Zucker rats pretreated with recombinant interleukin 6 (rIL-6). The mitotic cycle in hepatocytes was investigated by 4 different markers of regeneration representing distinct phases of mitosis (proliferating cell nuclear antigen [PCNA] = G(1) phase, bromodeoxy uridine [BrdU] = S phase, mitotic index, and regenerated liver weight = M phase). Obese Zucker rats had significantly decreased regenerative capacity compared with lean Zucker rats (PCNA, BrdU, mitotic index, regenerated liver weight) at days 1 and 2 after surgery. Four days after resection fatty animals showed an increase in the mitotic index indicating a delay of regeneration in steatotic livers. Animal survival after 70% hepatectomy was significantly decreased in obese rats compared with lean animals. Pretreatment of obese animals with rIL-6 normalized PCNA expression (G(1) phase) in steatotic hepatocytes but failed to increase DNA synthesis (BrdU, S phase), mitosis (mitotic index and regenerated liver weight, M phase), and animal survival. These results indicate major impairment of hepatic regeneration in steatotic livers. Two different blockages of regeneration must be present, one rIL-6 sensitive, at the level of IL-6 or upstream, and a second, rIL-6 resistant, at the level of G(1)/S-phase transition.     

Role of peroxisome proliferator-activated receptor-gamma (PPARgamma) during liver regeneration in rats

Background and Aim:  Peroxisome proliferator-activated receptor-gamma (PPARγ), a member of the nuclear receptor superfamily, is widely expressed in adipocytes and other tissues, including the liver. Several reports have shown that PPARγ activation induced cell-cycle arrest and apoptosis in tumor cells. We investigated the role of the PPARγ/ligand system and the effect of the PPARγ agonist during liver regeneration.
Methods:  Expression of PPARγ and serum levels of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) by enzyme immunoassay were evaluated in rats following partial hepatectomy (PH group). Further, the effect of the PPARγ agonist, pioglitazone, on liver regeneration (PH + PGZ group) was evaluated by proliferating cell nuclear antigen labeling index, relative liver weight, and expression of cell-cycle regulators.
Results:  The number of PPARγ-stained hepatocytes decreased at 24 h (PH, 15.8 ± 2.2%; sham, 35.5 ± 2.4%; P  < 0.001) and increased in the late phase of liver regeneration compared to the sham-operated group ( P  < 0.001 at 48–120 h). The peaks of serum 15d-PGJ2 (627.0 ± 91.1 pg/ml) and PPARγ expression (90.6 ± 3.1%) coincided in the late phase of liver regeneration. Also, oral administration of pioglitazone inhibited hepatocyte proliferation, in terms of the proliferating cell nuclear antigen (PCNA) labeling index and p27 expression during the late phase of liver regeneration, and caused a transient reduction in liver mass when compared to the PH group.
Conclusions:  These results indicate that the PPARγ/ligand system may be one of the key negative regulators of hepatocyte proliferation and may be responsible for the inhibition of liver growth in the late phase of liver regeneration.     

Mild hypothermia does not affect liver regeneration after partial hepatectomy in mice

Background: The use of mild hypothermia has been suggested to be therapeutically useful in treating acute liver failure. It is not known if hypothermia influences liver regeneration. Aim: To assess the effect of hypothermia on liver regeneration in mice. Methods: After partial (70%) hepatectomy (PHx), C57BL6/J mice were randomly assigned to either a hypothermic group or a normothermic group. Controlled mild hypothermia was maintained for up to 3 h after surgery. In addition, assessment of liver mass restitution was examined by studying the induction of key cell cycle proteins (cyclin A, D1 and E) and hepatocyte proliferation [assessment of proliferating cell nuclear antigen (PCNA) protein expression] by Western blotting and DNA synthesis by measuring 5‐bromo‐2‐deoxyuridine (BrdU) incorporation by immunohistochemical techniques 45 h after PHx. Results: Partial hepatectomy induced a vigorous proliferative response in the remnant livers of both groups of mice (normothermic and hypothermic groups), as evidenced by the induction of key cyclins, PCNA and incorporation of BrdU after PHx. The liver/body weight ratio and both cyclin and PCNA protein expression as well as BrdU incorporation did not differ between the regenerating livers of hypothermic and normothermic groups. Conclusion: Mild hypothermia does not influence liver regeneration in mice.     

Kinetics of liver regeneration in donors after living donor liver transplantation: A retrospective analysis of “2/3rd partial hepatectomy” model at 3 months

Background/Aim

Right lobe living donor (2/3rd partial hepatectomy) model is the best way to accurately study liver regeneration process in human beings. We aimed to study the kinetics of liver regeneration after 2/3rd partial hepatectomy in donors.

Methods

Retrospective analysis of prospectively maintained volumetric recovery data in donors was performed in 23 donors, who underwent 29 contrast-enhanced computed tomography within 3 months for various clinical indications.

Results

The absolute volumetric growth percentages were as follows: 37.60?±?21.74 at 1st week, 92?±?53.27 at 2nd week, 115.55?±?59.65 at 4th week, and 110.79?±?64.47 at 3 months. On sub-group analysis of our cohort, we found that 4.3%, 17%, 30.4%, and 39% donors attended ≥?90% volumetric recovery at 1st, 2nd, 4th week, and 3 months, respectively. One patient at 4th week revealed 128% volumetric recovery. There was one more patient who exceeded original total liver volumes (TLV) (111% of TLV) at 2.5 months. The serum bilirubin and INR values peaked at postoperative day (POD) 3rd and then started showing a downward trend from POD 5th onwards.

Conclusion

Our study is the first to document complete volumetric recovery in donors as early as 3 weeks. Two of the donors overshot their original TLV during the early regenerative phase.