DNA polymerases and Ki-67 nuclear antigen are induced in correlation with the resected mass of rat liver up to 90%

Background and aims: We studied the regeneration potential by measuring induction of DNA polymerases in the remnant rat liver after a partial hepatectomy (PHx) that is maximal but compatible with survival. Methods: The regenerating rat liver was obtained after the 90% PHx. The induction of activities of DNA polymerase α, δ, and ɛ were measured after partial purification. The Ki-67 nuclear antigen was also detected histochemically. These parameters were compared with those after both 30% and 70% PHx. Results: The 90% hepatectomy resulted in the strong inductions of DNA polymerase α, δ, and ɛ, at 48 h after operation, in association with increases in wet weight and total DNA in the remnant liver. The enzyme induction was much higher after 90% PHx than after 30% and 70% hepatectomy, in correlation with the resection volume. At 48 h after 90% hepatectomy, the Ki-67 positive cells increased up to 47.2% of hepatocytes in the remnant liver. Conclusion: The higher induction of replication enzymes by 90% hepatectomy reflects more cells entering mitogenic cell cycle, which supports the fast regeneration of the remnant liver. The number of proliferating hepatocytes is stringently controlled by an unknown mechanism sensing the mass of resected liver parenchyma. Received: 9 March 1999; In revised form: 2 August 1999 Accepted: 20 August 1999     

Decrease in regeneration capacity of rat liver after external biliary drainage.

In order to discover the effect of external biliary drainage on liver regeneration, we have produced a model system carrying cannula in the common bile duct of rat liver and examined the regeneration capacity of liver after partial hepatectomy under various conditions. Previously we have shown that hepatic cells proliferate by obstructive jaundice alone without partial hepatectomy [Terasaki et al; Jpn J Cancer Res 1991;82:170-175]. In the present study, we showed that DNA polymerase-alpha was induced by partial hepatectomy of rats suffering from obstructive jaundice and the induced level was similar to that of the normal regenerating liver. The level of DNA polymerase-alpha activity corresponded well to the liver regeneration capacity estimated by mitotic index. Contrary to our expectation, external biliary drainage for obstructive jaundice markedly suppressed the regeneration capacity of the remaining liver which was estimated by DNA polymerase-alpha activity, mitotic index and [3H]thymidine incorporation. The suppression may be due to the external biliary drainage itself because the liver regeneration of normal rats without jaundice was also suppressed by the biliary drainage. These results suggest that the external biliary drainage seriously suppresses the regeneration capacity of liver at least at the early stage of obstructive jaundice.     

Differences in biliary lipid excretion after major hepatectomy in obstructive jaundiced rats with preoperative internal,external, or no biliary drainage

Necessity of preoperative biliary drainage for patients with obstructive jaundice is still controversial. We recently reported that liver regeneration after major hepatectomy was better restored in a rat model of obstructive jaundice with preoperative internal biliary drainage than that without biliary drainage or with external biliary drainage. The aim of this study was to investigate the differences in biliary lipid excretion after hepatectomy in obstructive jaundiced rats with or without preoperative internal or external biliary drainage. After bile duct ligation for 7 days, rats were randomly divided into the three groups; obstructive jaundice-hepatectomy (OJ-Hx), internal biliary drainage-hepatectomy (ID-Hx), and external biliary drainage-hepatectomy (ED-Hx) groups. 70% hepatectomy and internal biliary drainage were carried out 7 days after biliary decompression in the latter two groups and without biliary decompression in the OJ-Hx group. On the day of and on days 1, 2, 3 and 7 after hepatectomy, the liver weight, DNA synthesis rate, biliary lipids excretion rates, and bile acid composition were determined. In the ID-Hx group, the DNA synthesis rate and relative liver weight were significantly higher than those of the OJ-Hx and ED-Hx groups. The excretion rates of biliary lipids were disturbed in the ED-Hx group compared with those in the ID-Hx group and the values in the OJ-Hx group were in-between the ID-Hx and ED-Hx group. The liver regeneration rate was significantly correlated with bile flow and excretion rates of biliary lipids. The maintenance of enterohepatic circulation of biliary lipids before hepatectomy may be important for the liver regeneration.     

阻塞性黄疸大鼠术前胆道内、外引流对肝细胞再生能力的影响

目的　探讨阻塞性黄疸大鼠肝叶切除术前胆道内、外引流对肝细胞再生能力的影响和机制。方法　将大鼠胆总管结扎 5d后 ,分别行胆道内、外引流 5d ,再行 70 %肝叶切除术。结果　胆道外引流组与内引流组和对照组大鼠相比 ,反映肝细胞再生能力的肝细胞核DNA含量、增殖细胞核抗原 (proliferatingcellnuclearantigen ,PCNA)指数、有丝核分裂指数 (mitoticindexMI)明显减低 (P <0 0 5 )。胆道外引流组肝细胞C met/HGF R基因表达也减低 (P <0 0 1)。结论　阻塞性黄疸大鼠肝叶切除术前胆道外引流对肝细胞再生能力有明显抑制作用 ;胆道外引流组肝细胞C met/HGF R基因表达减弱可能是该组肝细胞再生能力下降的重要因素。     

Preoperative internal biliary drainage is superior to external biliary drainage in liver regeneration and function after hepatectomy in obstructive jaundiced rats

OBJECTIVE: To examine the differences in regeneration rates and functions of the liver at the time of and after hepatectomy in obstructive jaundiced rats with preoperative external and internal biliary drainage. SUMMARY BACKGROUND DATA: The significance of biliary drainage before surgery is controversial in patients with obstructive jaundice. METHODS: After biliary obstruction for 7 days, rats were randomly divided into three groups: obstructive jaundice and hepatectomy (OJ-Hx), external biliary drainage and hepatectomy (ED-Hx), and internal biliary drainage and hepatectomy (ID-Hx). The OJ-Hx group underwent hepatectomy without biliary drainage; the other two groups underwent hepatectomy after biliary drainage for 7 days. At the time of hepatectomy, all rats were provided with internal biliary drainage. On days 0, 1, 2, 3, and 7 after hepatectomy, the DNA synthesis rate and the concentrations of adenine nucleotides and malondialdehyde in the liver were determined as markers of the hepatic regeneration rate, energy status, and lipoperoxide concentration, respectively. Portal endotoxin concentrations were measured and serum hyaluronic acid concentrations were determined as an indicator of hepatic endothelial function. RESULTS: The relative liver weight was significantly higher in the ID-Hx group than in the OJ-Hx group on days 1, 3, and 7 after hepatectomy and than in the ED-Hx group on days 1 and 2. The rate of hepatic DNA synthesis was significantly higher in the ID-Hx group than in the OJ-Hx and ED-Hx groups on day 1. The rate was similar in the ED-Hx and ID-Hx groups on day 2 but was significantly higher than in the OJ-Hx group. The hepatic malondialdehyde concentration was significantly higher on day 1 in the ED-Hx group than in the other two groups. It was lowest in the ID-Hx group throughout the study. Both biliary drainage procedures lowered the portal endotoxin concentration and serum hyaluronic acid concentration at the time of hepatectomy. The serum hyaluronic acid concentration was lowest in the ID Hx group. Hepatic adenine triphosphate concentrations and energy charge levels were similar among the three groups. CONCLUSION: Although both external and internal biliary drainage before hepatectomy improved serum liver function tests, portal endotoxin concentration, and serum hyaluronic acid concentration at the time of surgery, preoperative internal biliary drainage was superior to external drainage, as evidenced by the better liver regeneration and function after hepatectomy.     

Immediate increase of portal pressure, reflecting sinusoidal shear stress, induced liver regeneration after partial hepatectomy

The mechanisms whereby hepatocytes in the normal liver can be primed for replication following partial hepatectomy (PHx) are poorly understood. To determine whether "shear stress," which is induced by acute portal hypertension after PHx, is involved in liver regeneration, we studied liver regeneration in rats with splenic transposition (SPT) in which we can minimize the postoperative elevation of portal pressure. Rats underwent 70% PHx following splenic transposition or sham surgery and were killed at various time points to measure portal pressure and other factors. In the control groups, the portal pressure was significantly increased immediately after surgery, peaking at 48 h, and returning to near the preoperative levels by 168 h after PHx. In the SPT group, although portal pressure increased immediately, it decreased to the control levels 6 h after PHx and thereafter repeatedly increased. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels peaked at 24 and 6 h after PHx, respectively. Proliferative cell analysis was done using MIB-5 antibody, and there were no significant differences between the two groups. Furthermore, liver weight was restored in the same way in both groups. Taken together, the results suggest that an immediate increase in portal pressure is necessary for the initiation of liver regeneration. Received for publication on Jan. 20, 1999; accepted on Feb. 25, 1999     

Mechanism of liver regeneration after liver resection and portal vein embolization (ligation) is different?

Whether or not liver regeneration after portal branch embolization (PE) (ligation, PVL) in the non-embolized (ligated) lobe is by the same mechanism as regeneration in the remnant lobe after liver resection has been reviewed. Portal vein branch embolization and heat shock protein are then discussed. Tumor growth accelerated in the remnant liver after hepatectomy. In contrast, PE or PVL resulted in marked contralateral hepatic hypertrophy and significant reduction of tumor growth in the non-embolized (non-ligated) lobes. Follistatin administration significantly increased liver regeneration after hepatectomy in rats. In contrast, regeneration of non-ligated lobes after PVL was not accelerated by exogenous follistatin. Tumor growth also was not accelerated. The liver regeneration rate peaked at 48–72 h in the nonligated lobe after PVL, a delay of 24 h compared with the remnant liver after hepatectomy. In the postoperative early stage, the expression of activin βA, βC, and βE mRNAs was stronger in PVL than in hepatectomy. At 72 h the expression of activin receptor type IIA mRNA reached a peak in hepatectomy, but was significantly lower in PVL. Thus, regulation of activin signaling through receptors is one of the factors determining liver regeneration after hepatectomy and PVL. These serial experimental results imply that the mechanism of liver regeneration after portal branch ligation (embolization) is different from that after hepatectomy. Heat shock protein was induced in the liver experimentally by intermittent ischemic preconditioning and could play some beneficial role in the recovery of liver function after hepatectomy, even in cirrhotic patients. When heat shock protein following right portal vein embolization in both the embolized and non-embolized hepatic lobes was investigated in clinical cases, a two to fourfold increase in HSP70 was induced in the non-embolized lobe compared with the embolized lobe. Oral administration of geranylgeranylacetone (a non-toxic HSP inducer) suppressed inflammatory responses and improved survival after 95% hepatectomy by induction of HSP70 in rats.     

胆道梗阻大鼠肝切除术后胆汁内引流和外引流对肝功能及肝再生的影响

目的:比较胆汁内引流和外引流对胆道梗阻大鼠肝切除术后肝功能及肝再生的影响。方法:将SD大鼠随机分为胆汁内引流组(ID组)、胆汁外引流组(ED组)、对照组,ID组和ED组均行胆总管结扎,对照组行假手术,各组均于术后72 h行部分(70%)肝切除,ID组和ED组同时分别行胆汁内引流与胆汁外引流。分别在肝切除术后0、1、2、3、7 d收集大鼠血清与残余肝组织,检测肝功能指标、肝组织有丝分裂细胞数以及增殖细胞核抗原(PCNA)的表达,并计算各组肝切除术后7 d残肝质量/体质量比值。结果:与对照组比较,ID组和ED组肝切除术后各时间点,血清总胆红素(TBIL)与谷草转氨酶(AST)均明显升高,而白蛋白(ALB)水平明显降低(均P0.05);ID组与ED组间比较,除TBIL水平无统计学差异外(均P0.05),其他两项指标ID组均优于ED组(均P0.05)。与对照组比较,ID组和ED组核分裂细胞数在肝切除术后大多数时间点均明显降低(均P0.05),但ID组核分裂细胞数多于ED组,在肝切除术后2、3 d差异有统计学意义(均P0.05)。肝切除术后,ID组和ED组肝组织PCNA表达量升高的速度与幅度均低于对照组(均P0.05),ID组升高的程度与衰退的速度大于ED组(均P0.05)。与对照组比较,ID组和ED组在肝切除术后7 d的残肝质量/体质量比值均降低(均P0.05),ID组的残肝质量/体重比值明显高于ED组(P0.05)。结论:胆道梗阻的大鼠部分肝切除术后,胆汁内引流可以改善术后肝功能,促进残余肝脏再生。     

Experimental study on therapeutic plasmapheresis with the biliary decompression in the treatment of obstructive jaundice

The effectiveness of therapeutic plasmapheresis with the biliary decompression was evaluated using animal model in the treatment of obstructive jaundice. Plasma exchange (PE) using fresh frozen plasma was carried out with biliary decompression on canine jaundice model made by means of ligation and resection of bile duct. Routine biochemical analysis was performed following the PE and biliary drainage and the result was compared with the external biliary drainage group. Plasma level of total bilirubin decreased after PE and kept lower level while plasma level of bilirubin in external biliary drainage group decreased slowly. M-GOT and GOT level, those are the indicators of liver cell injury, was lower in PE group. Mitochondrial function of liver cell was evaluated following partial hepatectomy carried out two days after PE with biliary decompression on jaundiced rat. Mitochondrial respiratory control ratio and ADP/O ratio was improved in PE group. The effectiveness of PE is speculated as the combined mechanism of the removal of hepatotoxic factors in the jaundiced plasma and the addition of hepatotrophic factors within the fresh frozen plasma. These results support the effectiveness of PE to shorten the biliary drainage period and to improve the hepatic function for perioperative management.     

Effect of partial portal vein ligation on hepatic regeneration

To evaluate the effect of portal hypertension and diminished portal venous blood flow to the liver on hepatic regeneration, male rats were subjected to partial portal vein ligation and subsequently to a two-thirds partial hepatectomy. The levels of ornithine decarboxylase activity at 6 h after partial hepatectomy were greater (p less than 0.001) in the rats with prior partial portal vein ligation than in those without portal hypertension. The rats with prior partial portal vein ligation also had greater (p less than 0.005) levels of thymidine kinase activity at 48 h after partial hepatectomy than did those without portal hypertension. Hepatic sex hormone receptor activity was not affected by prior partial portal vein ligation either before or after partial hepatectomy. The reductions in both estrogen and androgen receptor activity observed in the hepatic cytosol after partial hepatectomy were similar to those observed in control animals. These data indicate that animals with portal hypertension having a diminished hepatic portal blood flow have a normal capacity to regenerate hepatic mass following a hepatic resection.     

Effect of splenectomy on liver regeneration and polyamine metabolism after partial hepatectomy

The effect of splenectomy on hepatic ornithine decarboxylase (ODC) induction, DNA synthesis, and mitosis of hepatocytes was studied in rat liver after partial hepatectomy. ODC activity markedly increased in the early stages of liver regeneration, and the increase in the activity was significantly enhanced in splenectomized rats. Splenectomy specifically induced ODC since tyrosine aminotransferase and general protein synthesis were not affected. Splenectomy also enhanced increase in hepatic polyamines, DNA synthesis, and mitosis in regenerating liver. The results suggest that splenectomy affects liver regeneration after partial hepatectomy by enhancing induction of ODC activity, which is an important biochemical event in the early stage of liver regeneration.     

Effect of portal hemodynamics on liver regeneration studied in a novel portohepatic shunt rat model

BACKGROUND: The role of portal hemodynamics on liver regeneration after partial hepatectomy is not fully understood. The aim of our study was to characterize the effects of portal hemodynamics using a novel rat model. METHODS: We established a rat model of a portohepatic shunt with a 70% hepatectomy (PHS model), in which the portal pressure remained stable during and after the 70% hepatectomy. To assess the effect of portal hemodynamics on liver injury and regeneration in the first 24 hours, we compared PHS rats with those with a simple 70% hepatectomy. RESULTS: Biochemical and histopathologic changes were similar between the 2 groups. Liver weight increased in the control, whereas it did not in the PHS group (P = .0021). Hepatocytes were enlarged in the control but not in the PHS group, although DNA synthesis was similar in both groups. Apoptotic hepatocytes increased markedly in PHS at 24 hours, whereas minimal apoptosis was noted throughout the course of the study in the control group. Hepatocyte growth factor increased similarly, except that it was not activated in PHS. CONCLUSIONS: Our results suggested that a portal hyperdynamic state early after a 70% hepatectomy was necessary for liver regeneration through activation of hepatocyte growth factor, promoting hepatocyte hypertrophy and avoiding apoptosis, while DNA synthesis in hepatocytes was independent of portal hemodynamics.     

Beneficial effects of arterialization of the portal vein on extended hepatectomy

BACKGROUND: Extended hepatectomy may result in postoperative liver failure. The aim of this study was to evaluate the effects of arterialization of the portal vein on oxygen supply, hepatic energy metabolism and liver regeneration after extended hepatectomy. METHODS: Portal haemodynamics were evaluated 0 or 10 days after arterialization of the portal vein in three experimental groups: 85 per cent partial hepatectomy, 85 per cent partial hepatectomy 10 days after arterialization of the portal vein and 85 per cent partial hepatectomy 10 days after ligation of the hepatic artery. Survival rates, weight of the regenerating liver, levels of adenine nucleotides and hepatic energy charge were assessed. RESULTS: Arterialization of the portal vein caused a significant increase in partial pressure of oxygen and oxygen saturation. Portal blood flow 10 days after arterialization was significantly increased. Survival rate and weight of the regenerating liver in the group with arterialization of the portal vein were significantly higher than those in the other two groups. The group with arterialization of the portal vein showed the highest levels of adenosine 5'-triphosphate. CONCLUSION: The increase in portal blood flow and oxygen supply produced by arterialization of the portal vein has beneficial effects on hepatic energy metabolism and liver regeneration, and leads to improved survival after experimental extended hepatectomy.     

Portal blood flow regulates volume recovery of the rat liver after partial hepatectomy: molecular evaluation

BACKGROUND/AIM: Liver regeneration is a finely tuned process that is closely regulated by multiple cell cycle steps. Although the portal blood flow affects liver regeneration, the molecular mechanism by which the blood flow regulates gene expression and liver function is largely unknown. The aim of this study was to investigate the molecular effect of portal blood flow on hepatocyte proliferation and gene regulation during liver regeneration. MATERIALS AND METHODS: We developed a simple surgical rat model to investigate the relation between portal blood flow and liver regeneration by partially ligating the portal trunk with 8-0 Proline sutures under microscopy to reduce the blood flow by 40%. We investigated recovery of liver volume, DNA synthesis, and gene expression associated with cell cycle regulators, comparing partially hepatectomized (PH) rats without (PH group; n = 30) and with partial portal ligation (PHPL group; n = 30) for 7 days after the operation. RESULTS: The hepatic tissue blood flow and the recovery ratio between liver weight and body weight in the PHPL group were significantly lower than in the PH group after hepatectomy. The peak 5-bromo-2'-deoxyuridine labeling index in the PHPL group was delayed and weak compared with the PH group. The expression of CT-1 and cyclin D, E, and B mRNAs indicated that the liver regeneration in the PHPL group was delayed and weak. In addition, there was reciprocal expression of C/EBPalpha and C/EBPbeta mRNAs, an observation supported by their nuclear protein levels. Furthermore, the cytochrome P-450 protein level in the PHPL group was higher than that in the PH group 1 day after hepatectomy. CONCLUSION: The portal blood flow regulates the activity of liver regeneration and the gene expression associated with cell cycle regulators, while the functions are maintained.     

Kupffer cell-mediated inhibition of liver regeneration after combined hepatectomy and pancreatectomy

Recently, simultaneous hepatectomy and pancreatoduodenectomy has been performed for the treatment of some biliary tract cancers in Japan. Postoperative hepatic failure is a common and potentially fatal complication. The aim of this study was to examine the reduction in the rate of liver regeneration after 70% hepatectomy (Hx) alone or in combination with 70% pancreatectomy (HPx). Male Sprague-Dawley rats underwent hepatectomy or simultaneous hepatectomy and pancreatectomy. The ratio of liver weight to body weight, the labeling index of hepatocytes in vivo, and DNA synthesis of the hepatocytes and/or Kupffer cells in primary culture were analyzed. The ratio of liver weight to body weight and the labeling index in HPx rat were found to be significantly lower than those values in Hx rats. There were no significant differences in plasma alanine aminotransferase levels between the two groups. The inhibitory effect on DNA synthesis was observed with coculture of hepatocytes and Kupffer cells when the portal plasma obtained 1 hour after operation was added. We further observed that the conditioned medium of Kupffer cells stimulated by the addition of the portal plasma that was obtained 1 hour after HPx inhibited DNA synthesis of hepatocytes. This effect was abolished after incubation at 56° C for 30 minutes. These results strongly suggest the existence of a growth inhibitory factor in portal plasma after HPx. This heat-labile growth inhibitory factor was released from Kupffer cells and would appear to act on hepatocytes in a paracrine manner. Supported by the Kanae Foundation for Life and Sociomedical Science, Japan. Presented at the Thirty-Eighth Annual Meeting of The Society-for Surgery of the Alimentary Tract, Washington, D.C., May 11–14, 1997.     

Role of shear stress and immune responses in liver regeneration after a partial hepatectomy

This report reviews studies addressing the new concepts in liver regeneration after a partial hepatectomy (PHx). The review begins with an overview of the immunologic mechanisms of liver regeneration after PHx, especially regarding Kupffer cells and extrathymic T cells of the regenerative liver in the cell-mediated immunity, based on major histocompatibility complex I and II antigens. Attention is then devoted to “on and off” studies in liver regeneration after PHx, by hypothesizing the shear stress based on the fact that the portal flow against hepatocytes or sinusoidal endothelial cells triggers their regeneration after a partial hepatectomy and controls the volume of the regenerating liver by the stimulating the cell surface modulator (CSM) of hepatocytes and sinusoidal endothelial cells (SEC). We propose that the acute elevation of shear stress after PHx influences the adhesion between SEC and intrahepatic leukocytes. These concepts are expected to positively contribute to the future research on liver regeneration after PHx.     

不同引流方式对梗阻性黄疸大鼠部分肝切除术后肝再生的影响

目的探讨不同引流方式对梗阻性黄疸大鼠部分肝切除术后肝再生的影响。方法建立梗阻性黄疸70％部分肝切除sD大鼠模型。随后将120只sD大鼠按照随机数字表法分为对照组：行肝中、左叶切除;内引流组：于扩张胆管和十二指肠间置管引流;外引流组：于扩张胆管置管,导管另-端从腹腔引出。每组40只大鼠。内引流组和外引流组引流7d后行肝中、左叶切除,于术后0、1、2、4、12、24、48、72h收集3组大鼠血液及肝脏组织标本,测定肝再生率、有丝分裂指数。采用免疫组织化学染色法观察肝脏组织增殖细胞核抗原（PCNA）及信号传导与转录激活因子3（STAT3）的表达,ELISA法检测血清TNF．OL、IL-6水平,RT．PCR测定肝脏组织TNF—OLmRNA和IL-6mRNA的表达。组间比较采用单因素方差分析,两两比较采用SNK检验。结果部分肝切除术后72h内引流组sD大鼠肝再生率为94．86％±12．72％,显著高于外引流组的62．39％±8．01％和对照组的45．77％±5．41％（F=33．62,P〈0．05）。3组大鼠肝脏组织有丝分裂指数和PCNA水平均于12h明显升高,内引流组有丝分裂指数和PCNA水平均于24h达到高峰,分别为24．47％±4．01％和88．1％±9．2％,对照组和外引流组于48h达到高峰,分别为15．80％±1．08％和58．3％±5．8％、18．40％±1．12％和70．2％±6．9％。内引流组有丝分裂指数和PCNA水平峰值显著高于对照组和外引流组（P〈0．05）。内引流组STAT3表达于术后4h达到高峰,为42．6％±3．6％,对照组和外引流组分别于术后12h达到高峰,分别为22．9％±2．0％和29．2％±3．7％。内引流组STAT3表达峰值显著高于对照组和外引流组（P〈0．05）。内引流组TNF—d和IL-6水平均于术后12h达到高峰,分别为（227±23）U／L和（256±32）U／L;对照组和外引流组TNF—d和IL-6水平均于术后24h达到高峰,分别为（309±41）U／L和（388±40）U／L、（287±30）U／L和（346±33）U／L,内引流组术后0、1、2、4、12、24、48、72hTNF-0l和IL-6水平显著低于相同时相点对照组和外引流组（P〈0．05）。对照组、内引流组和外引流组大鼠肝组织TNF-dmRNA表达均于术后4h达到高峰,分别为0．92±0．14、0．39±0．05、0．80±0．15,IL-6mRNA于术后12h达到高峰,分别为0．79±0．07、0．38±0．06、0．63±0．10,内引流组术后0、1、2、4、12、24、48、72hTNF—dmRNA和IL-6mRNA表达显著低于相同时相点对照组和外引流组（P〈0．05）。结论内、外引流均可改善梗阻性黄疸大鼠剩余肝脏的再生能力,但内引流效果更明显。内引流术可能通过降低TNF-α和IL-6水平,影响STAT3表达而改善梗阻性黄疸大鼠剩余肝脏的再生能力。     

The nonportal origin of the factors initiating hepatic regeneration.

To determine the site of origin of the factors that initiate deoxyribonucleic acid (DNA) synthesis in the liver after partial hepatectomy, normal rats were cross-circulated with totally hepatectomized rats. Half of the hepatectomized rats had also undergone excision of all of the portal organs. After 48 hours of cross-circulation, active DNA synthesis and other evidences of hepatic regeneration were found in normal rats cross-circulated with the hepatectomized portally eviscerated rats. This demonstrates that a blood-borne factor that does not arise from the portal organs is capable of initiating hepatic regeneration. When a normal rat was cross-circulated with a hepatectomized rat with the portal organs still present, hepatic regeneration occurred but was significantly less than when the portal organs had been removed. It is postulated that under these experimental conditions portal factors from the normal rat have a permissive role that allows active regeneration when initiating factors are furnished from the hepatectomized rat. Additional portal organs in the hepatectomized rat decreased DNA synthesis, possibly by alterations of the insulin/glucagon ratio.     

Lack of intestinal bile results in delayed liver regeneration of normal rat liver after hepatectomy accompanied by impaired cyclin E-associated kinase activity

BACKGROUND: The importance of bile in liver regeneration after hepatectomy is unknown, although we have recently shown that preoperative internal biliary drainage is superior to external biliary drainage for liver regeneration in obstructive jaundiced rats. This study examined the hypothesis that the presence or absence of bile in the intestinal tract modulates cyclins and cyclin-dependent kinases after hepatectomy in rats. METHODS: In male Wistar rats, bile was drained externally (ED group) or into the duodenum (ID group) for 7 days before 70% hepatectomy. Relative liver weight, DNA synthesis rate, and proliferating cell nuclear antigen labeling index were determined at the time of hepatectomy (day 0) and on days 1, 3, and 7 after hepatectomy. Posthepatectomy expressions of cyclin D1 and E and of cyclin D1- and E-associated kinases were serially analyzed. Hepatic function tests were performed. RESULTS: No significant difference in liver function was found between the 2 groups at hepatectomy except for the lower albumin level in the ED group. The relative liver weight was lower in the ED group than in the ID group on day 3 after hepatectomy (ED, 2.58% +/- 0.06%; ID, 2.84% +/- 0.08%; P <.05). Both the DNA synthesis rate and proliferating cell nuclear antigen labeling index in the ED group (77 +/- 36 disintegrations per minute/microg DNA and 8.3% +/- 1.9%, respectively) were lower than those in the ID group (262 +/- 50 disintegrations per minute/microg DNA and 21.6% +/- 5.6%, respectively) on day 1 after hepatectomy (P <.05, respectively). Cyclin D1-associated kinase activity and cyclin D1 expression were not significantly different between the 2 groups. Cyclin E-associated kinase activity was lower in the ED group than in the ID group at 18 hours after hepatectomy (ED, 84% +/- 17%; ID, 146% +/- 28% of the value at 0 hour in the ID group; P <.05), although expressions of cyclin E and p27 binding to cyclin E were not significantly different between the 2 groups. CONCLUSIONS: These results suggest that the absence of bile in the intestine delays liver regeneration associated with cyclin E-associated kinase inactivation after hepatectomy.