Possible inhibitory mechanism of liver regeneration through non-parenchymal cells after combined hepatectomy and pancreatectomy

BACKGROUND: Recently, simultaneous hepatectomy (Hx) and pancreaticoduodenectomy have been performed in the treatment of biliary tract cancer. Postoperative hepatic failure is a common and potentially fatal complication. The aim of this study was to examine the reduced rate of liver regeneration after 70% Hx alone or in combination with 70% pancreatectomy (HPx). MATERIALS AND METHODS: Male Sprague-Dawley rats underwent Hx or combined Hx and Px. The ratio of liver-body weight, labeling index of hepatocytes in vivo, and DNA synthesis of hepatocytes and/or Kupffer cells in primary culture were analyzed. RESULTS: The ratio of liver-body weight in HPx rats was found to be significantly lower than that in Hx rats from 12 hours to 72 hours after surgery. There was no difference in blood glucose or ALT levels between the two groups. An inhibitory effect on DNA synthesis was observed in cocultured hepatocytes and Kupffer cells when portal plasma obtained one hour after surgery was added. We further observed that conditioned medium of Kupffer cells stimulated by portal plasma obtained one hour after HPx inhibited DNA synthesis by hepatocytes. This effect was abolished after incubation at 56 degrees C for 30 min. CONCLUSIONS: These results clearly indicate the existence of a growth inhibitory factor in portal serum after HPx. This heat-labile growth inhibitory factor was released from Kupffer cells stimulated by portal plasma after HPx and appears to act on hepatocytes in a paracrine manner.     

Hepatic protein synthesis in the regenerating rat liver after hepatopancreatectomy

To evaluate the effects of hepatopancreatectomy on the regenerative process of the liver, the serum protein changes, hepatic protein synthesis (HPS), and bromodeoxyuridine (BrdU) labeling index were measured in rats. Sprague-Dawley rats were divided into four groups according to the type of resection: A simple laparotomy was performed in the sham group; 68% of the liver was excised in the Hx group; 45% of the pancreas was excised in the Px group; and 45% of the pancreas and 68% of the liver were excised simultaneously in the HPx group. Serum total protein and albumin levels were significantly lower in the HPx group compared to the other three groups on postoperative day (POD) 3 (P<0.05). HPS was markedly increased in the Hx and HPx groups. In the Hx group, it was significantly higher, peaking on POD 2, compared to the HPx group (P<0.05), while in the HPx group, it was significantly higher compared to the Hx group (P<0.05), peaking on POD 3. The BrdU labeling index, as a marker of DNA synthesis, was significantly suppressed in the HPx group on POD 1 compared to the Hx group (P<0.05). Thus, compared to hepatectomy alone, hepatopancreatectomy suppresses DNA synthesis, causing a delay in the increase of protein synthesis in the regenerating liver, resulting in a more marked decrease in the serum protein level.     

Morphological and functional changes after portal vein occlusion in rats

We investigated morphological and functional changes after portal vein occlusion in rats. Portal branches for the median and left lateral lobes were ligated, after which the lobes were examined micromorphologically. After embolization of the same branches, regenerative capacity was evaluated in normal livers and in livers with CCl₄-induced cirrhosis. Indocyanine green elimination, antithrombin III activity, and Kupffer cell density were also investigated. In another set of rats, the embolized lobes were resected 0, 2, 4, or 7 days after portal vein embolization (PVE), and endotoxin was injected intravenously 48h after each hepatectomy. In the ligated lobes, apoptotic hepatocytes were detected mainly around a widespread necrotic area on day 2, and among normal hepatocytes on day 7. In the nonembolized livers of control rats, increases were noted in liver weight, ornithine decarboxylase (ODC) activity, DNA synthesis, and mitosis of hepatocytes. In the cirrhotic livers, ODC activity was stimulated in a fashion similar to that seen in control liver, but DNA synthesis and weight change was delayed, although not significantly. On days 2, 4, 7, and 14 PVE, Kupffer cell density was about twice that seen in rats before PVE. Endotoxin-induced liver injury was slight if the rats had received PVE 4-7 days before the hepatectomy.     

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.     

Significance of sonic hedgehog signaling after massive hepatectomy in a rat

Purpose

To clarify the functional involvement of hedgehog signaling, especially sonic hedgehog (Shh) and glioma-associated oncogene (Gli)-1 which are known to play an important role in embryonic development and cancer, in the regeneration of a hepatectomized rat liver.

Methods

Six-week-old male Wistar rats were subjected to 70 or 90 % hepatectomy (Hx). Animals were killed at 24, 48 and 72 h after Hx. The liver/body weight ratio was measured as an index of regeneration. Formalin-fixed liver samples were embedded in paraffin, stained for immunohistochemistry with proliferating cell nuclear antigen (PCNA) antibody, and the labeling index was calculated. Immunohistochemistry was also performed with Shh and Gli-1 antibodies.

Results

The liver/body weight ratio gradually increased in both the 70 and 90 % Hx, groups. The hepatocytes were strongly stained for PCNA at 24 h after Hx. Non-parenchymal cells were gradually stained by PCNA from 24 to 72 h after Hx. Shh and Gli-1 expression in hepatocytes was higher after 24 h than at other times and then gradually decreased. Shh and Gli-1 expression in non-parenchymal cells increased gradually, and was found mainly in liver zone I at 72 h after 70 and 90 % Hx.

Conclusions

The expression of both markers suggested that Shh signaling contributes to tissue reconstruction after Hx.     

Hepatocyte growth factor supply accelerates compensatory hypertrophy caused by portal branch ligation in normal and jaundiced rats.

BACKGROUND: Hepatocyte growth factor (HGF), first identified as the most potent mitogen for hepatocytes, significantly stimulates liver regeneration after hepatectomy. In this report, we examined whether HGF is also useful in accelerating compensatory hypertrophy caused by portal branch ligation in normal and jaundiced rats. MATERIALS AND METHODS: Normal and reversible obstructive jaundiced rats underwent portal ligation of the left lateral and median branches, which supply approximately 70% of the total volume of the liver. Simultaneously, the animals were continuously treated with either recombinant human HGF (rhHGF) or vehicle alone via an intraperitoneally implanted osmotic pump. Two and four days after portal ligation, the degree of compensatory hypertrophy in unoccluded lobes was examined by measuring the wet weight ratios of the unoccluded lobes to the whole liver and the 5-bromo-2'-deoxyuridine labeling index of hepatocytes in each group. RESULTS: The HGF treatment significantly increased the wet weight ratios and the DNA synthesis in nonoccluded lobes 2 and 4 days after portal ligation in both normal and jaundiced rats. Moreover, rhHGF supply promptly decreased serum total bilirubin level in jaundiced rats. CONCLUSIONS: Continuous rhHGF administration not only accelerates compensatory hypertrophy in normal and jaundiced rats but also ameliorates hyperbilirubinemia in jaundiced rats.     

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.     

Stimulation of liver regeneration after hepatectomy in mice by injection of bone marrow mesenchymal stem cells via the portal vein

Aim

To investigate whether mouse bone marrow mesenchymal stem cells (BMC) stimulate liver regeneration after partial hepatectomy.

Methods

Isolated BMCs were purified by density gradient centrifugation. We performed a 70% hepatectomy in male BALB/c mice followed by injection of BMCs into the portal vein (PV-BMC group), or the tail vein (IV-BMC group), or of saline into the portal vein (control group).

Results

The wet weight of the liver remnant increased significantly in the PV-BMC group at 3 and 5 days after hepatectomy compared with the IV-BMC and control groups. The Ki-67 labeling index revealed that the increase to result from stimulation of DNA synthesis. The constitutive interleukin-6 and hepatocyte growth factor mRNAs in the remnant liver tended to increase in the PV-BMC group at 3 days after hepatectomy.

Conclusions

These results demonstrated that BMC injection into the portal vein enhanced liver growth after partial hepatectomy in mice.     

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.     

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.     

大鼠肝、胰十二指肠联合切除残肝肝细胞生长因子表达的研究

目的 用实验动物模型同时切除肝脏、胰腺及十二指肠，以探讨肝细胞生长因子(HGF)对残肝再生的影响。方法 60只SD大鼠被随机分为4组：①68％肝切除组；②68％肝叶切除加50％胰腺切除组；③68％肝叶切除加十二指肠切除组；④68％肝叶切除、加50％胰腺切除加近端十二指肠切除组。每组中3只大鼠分别于术后12、24、48、72和168h处死并采集肝脏样本，计算肝再生率。切除的肝脏组织用RT-PCR技术检测HGF在术后不同时间的表达，并与免疫组化法检测的肝细胞增殖细胞核抗原(PCNA)进行对比研究。结果 68％肝切除组残肝HGF的表达逐渐增强，24h达到高峰，随后逐渐下降，168h时达最低水平。而肝、胰切除，肝十二指肠切除和肝、胰十二指肠切除可显著减少残肝细胞HGF的表达，并使HGF的表达延迟至术后48h。结论 HGF可促进肝脏切除术后残肝的再生反应，而起源于胰腺和十二指肠外分泌腺的其他因素亦对HGF的表达起显著的调节作用，从而影响肝细胞的增殖。     

Investigation of lipid peroxidation in regenerating rat liver]

The purpose of this study was to estimate the effects of lipid peroxidation in regenerating rat liver. Partial 70% hepatectomy was performed in rat according to Higgings and Anderson. EPC (alpha Toc: Ascorbic acid = 6:4, radical scavenger) was injected intravenously (5mg/kg weight) one hour before operation. Lipid peroxidation in regenerating liver reached a peak at 24 hours after operation. The administration of EPC markedly suppressed the increase of lipid peroxide in the plasma and remnant liver and that of GPT after hepatectomy, with subsequent good liver regeneration ratio. Moreover, the pretreatment with EPC remarkably elevated the activity of thymidine kinase (index of DAN synthesis). The EPC administration had not notable effects on the level of plasma ketone body ratio in animal but pathologically caused early advent of glycogen granule in the remnant liver tissue after partial hepatectomy, which reflected restoration of mitochondrial energy level. The results of the present study suggest that scavenger may be useful not only for impairment of liver dysfunction but also for recovery of mitochondrial energy level and DNA synthesis after liver resection.     

Effect of portal branch ligation on liver regeneration in the rat

GOAL: The aim of this study was to assess liver regeneration after partial portal ligation. METHODS: 70% partial portal occlusion was obtained by ligation of the left portal vein branch. Total liver weight ratio were measured 96 hours after partial portal occlusion and in sham operated animals. The kinetics of hepatocytes division was evaluated by measuring the incorporation of 5-bromo-21-deoxyuridine into replicating cells at various time points by immunohistochemistry. RESULTS: Partial portal occlusion did not alter the total liver weight 96 hours after surgery. It resulted in atrophy of the ligated lobes and hypertrophy of the lobes with preserved portal flow. Hypertrophy was associated to an increase of the percentage of replicating hepatocytes. The replication rate was maximum at 28 hours with a peak at 12.5% and was prolonged beyond the 48th hour. CONCLUSIONS: Partial portal occlusion results in major and prolonged regeneration process in the liver lobes with preserved portal flow.     

Gadolinium pretreatment decreases survival and impairs liver regeneration after partial hepatectomy under ischemia/reperfusion in rats

BACKGROUND: Modulation of Kupffer cell functions by treatment with gadolinium chloride protects the liver against reperfusion injury. However, its effect on liver regeneration after hepatectomy under ischemia/reperfusion has not been studied. Using a common clinical ischemia/reperfusion technique, we examined the effect of gadolinium on liver regeneration after hepatectomy in rats. METHODS: After an initial 15-minute ischemia and 15-minute reperfusion, 70% hepatectomy was performed during the second 15-minute ischemia period in gadolinium-pretreated (gadolinium group) and saline solution--pretreated (control group) rats. The 24-hour survival rate, relative liver weight, DNA synthesis rate, and hepatic adenosine triphosphate level were examined immediately after hepatectomy and on postoperative days (PODs) 1, 2, 3, and 7. Serum levels of total bilirubin, glutamic pyruvic transaminase, and endotoxin were also measured. RESULTS: The 24-hour survival rate was significantly lower in the gadolinium group (67%) than in the control group (100%). On POD 1, the relative liver weight and DNA synthesis rate were significantly lower in the gadolinium group than in the control group. On POD 1, serum total bilirubin and endotoxin levels were significantly higher in the gadolinium group than in the control group. Immediately after hepatectomy, the hepatic adenosine triphosphate level was significantly lower in the gadolinium group than in the control group. CONCLUSIONS: Under ischemia/reperfusion, gadolinium pretreatment impairs liver regeneration and energy status after hepatectomy and decreases postoperative survival.     

Effect of splenectomy on hepatic regeneration in rats

The effect of splenectomy on hepatic regeneration after partial hepatectomy was investigated in splenectomized and non-splenectomized rats. The results were as follows: The liver weight per body weight after partial hepatectomy increased significantly at 2 and 4 days in splenectomized group compared with non-splenectomized one. The rates of 3H-thymidine uptake in the regenerating liver cells at 24 hours after partial hepatectomy were more enhanced in splenectomized group than in non-splenectomized one. Thymidine kinase activity of the regenerating liver at 24 hours after partial hepatectomy in splenectomized rats was significantly higher than those in non-splenectomized rats. Both mitotic indices and labeling indices at 24 hours after partial hepatectomy in splenectomized rats were significantly higher than those in non-splenectomized group. The cells of mitotic stage were distributed mainly periportal area. From those results, it is suggested that the spleen has some inhibitory factors on hepatic regeneration after partial 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.     

Effect of anticancer agents on cell cycle of regenerating hepatocytes in rats.

The effect of three anticancer agents, cisplatin, doxorubicin, and mitomycin, on liver regeneration after 70% partial hepatectomy in rats was investigated by total DNA content of the liver and flow cytometric analysis of hepatocyte nuclei using two-color staining of anti-bromodeoxyuridine monoclonal antibody and propidium iodide. Total DNA content of regenerating liver 7 days after hepatectomy showed significant suppression of regeneration by these agents (P less than 0.01). The inhibitory effects of the agents on the cell cycle of hepatocytes by flow cytometric analysis were (1) a delay of the peak or a decrease in the proportion of S phase nuclei and/or (2) polyploidization of the nuclei, demonstrated by accumulation of 8c and occasionally 16c nuclei, of which the DNA contents were four and eight times as much as that of diploid (2c) cell nuclei, respectively. The former (1) suggests G0 or G1 phase block, and the latter (2) G2 phase block. In terms of total DNA content of regenerating liver, the inhibitory effect was most prominent in the cisplatin-administered groups. The polyploidization of nuclei was most remarkable in the mitomycin-administered groups. Although the total DNA content recovered to the level of control at 6 weeks after hepatectomy, the polyploidization effect persisted in the drug-administered groups. These agents had no cytocidal action on proliferating hepatocytes as can be seen from the aspartate aminotransferase and alanine aminotransferase serum levels. We conclude that in a short-term observation, the anti-cancer agents significantly inhibit liver regeneration, although the inhibitory effect on DNA synthesis does not last long.(ABSTRACT TRUNCATED AT 250 WORDS)     

Jejunectomy can reduce excessively elevated portal pressure after major hepatectomy in beagle dogs

A number of factors can lead to the life-threatening liver dysfunction in the aftermath of an extended hepatectomy. Prominent among them is the high portal pressure induced by the concentrated flow of the entire stream of portal blood toward the small remnant liver. Twelve beagle dogs were randomly divided into group A (n=6, 70% hepatectomy) and group B (n=6, 70% hepatectomy after jejunectomy). Three dogs in each group were euthanized at 1 or 4 weeks after the operation and examined to evaluate hemodynamic changes, liver functions, and liver histology. One hour after the hepatectomy, the animals in group B exhibited a significantly lower portal pressure (P=0.002) and significantly higher hepatic arterial flow (P=0.004) than the animals in group A. As more time passed, the total hepatic flow and hepatic tissue flow both rose up to levels significantly higher than those in group A (P=0.037 and P=0.025, respectively). The alkaline phosphatase, total protein, albumin, and anti-thrombin III were all significantly better in group B than in group A on the 1st post-operative day. Liver specimens biopsied at 1 h after the hepatectomy showed significantly more swelling of the hepatocytes in group A than in group B. In addition, an immunohistochemical study using the TUNEL method for liver biopsy on the seventh post-operative day revealed numerous positive cells in group A but few in group B. Our results suggest that the portal pressure control by the enterectomy can forestall dysfunction of the remnant liver after extended hepatectomy, especially during the early post-operative period.     

Regulation of hepatocyte engraftment and proliferation after cytotoxic drug-induced perturbation of the rat liver

BACKGROUND: Perturbations in specific liver cell compartments benefit transplanted cell engraftment and/or proliferation. We analyzed whether cytotoxic drugs interfering with the integrity of genomic DNA or cell division could be useful for liver cell transplantation. METHODS: We used dipeptidyl peptidase IV deficient (DPPIV-) rats as recipients of syngeneic F344 rat hepatocytes. Rats were pretreated with doxorubicin, irinotecan, or vincristine prior to cell transplantation and synergistic liver perturbations were induced by drug administration followed by partial hepatectomy or carbon tetrachloride treatments. Transplanted cells were identified by DPPIV histochemistry and cell engraftment and proliferation were analyzed morphometrically. Perturbations in endothelial, Kupffer cell, and hepatocyte compartments were analyzed by electron microscopy, carbon incorporation, and blood tests, respectively. RESULTS: Cell engraftment was improved in rats treated with doxorubicin but not with irinotecan or vincristine. Doxorubicin disrupted endothelial cells for up to seven days without causing Kupffer cell or hepatocellular toxicity. Neither doxorubicin nor vincristine induced liver repopulation in animals up to three months, including after partial hepatectomy or carbon tetrachloride-induced additional liver injury. CONCLUSIONS: Doxorubicin-induced hepatic endothelial damage enhanced cell engraftment, which should be useful in cell therapy strategies.