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Neutrophil-mediated sinusoidal endothelial cell injury after extensive hepatectomy in cholestatic rats.

The aim of this study was to assess the hypothesis that hepatic failure after extensive hepatectomy in patients with obstructive jaundice (OJ) may be mediated by polymorphonuclear neutrophils (PMN). In the OJ group, rats underwent a partial hepatectomy of 78% after 2 weeks of cholestasis and subsequent external biliary drainage for 5 days. In the sham-operated control group, rats were partially hepatectomized 19 days after the sham surgery. The concentration of the serum cytokine-induced neutrophil chemoattractant (CINC), which is homologous with the growth-related oncogene (gro) product, a member of the human interleukin (IL)-8 family, and a major neutrophil chemotactic factor in rats, increased concomitantly with accumulation of PMNs in the hepatic sinusoids during cholestasis and subsequent external drainage. However, changes in the serum purine nucleoside phosphorylase (PNP)/alanine transaminase (ALT) ratio as a marker of sinusoidal endothelial cell (SEC) injury showed no significant differences between the two groups. Intercellular adhesion molecule-1 (ICAM-1) expression on SECs was not affected by cholestasis and external drainage. After partial hepatectomy, the serum CINC concentration immediately elevated more prominently in the OJ group than in the sham-operated control group, and accumulation of PMNs in the sinusoids was more obvious and prolonged in the former. ICAM-1 expression was enhanced in both groups with a peak between 24 and 48 hours after partial hepatectomy. At this peak period, a significantly higher PNP/ALT ratio was observed in the OJ group. These results suggest that accumulation of PMNs in the sinusoidal space and ICAM-1 expression on SECs might be closely associated with the development of SEC injury after extensive hepatectomy in cholestasis.

Alanine Transaminase↗

Hepatic venous hemoglobin oxygen saturation predicts regenerative status of remnant liver after partial hepatectomy in rats.

This study was designed to evaluate the use of hepatic venous hemoglobin oxygen saturation (ShVO2) as an indicator of hepatic oxygen supply-demand relation and also regenerative status of the liver after partial hepatectomy in rats. We assessed the ShVO2 levels for 7 days, as well as hepatic hemodynamics, oxygen consumption, DNA synthesis and energy charge of the remnant liver for 3 days after 50% hepatectomy or sham operation. Total hepatic oxygen consumption (HVO2) per liver weight, hepatic oxygen extraction ratio (HO2ER), and DNA synthesis were significantly elevated at days 1 and 3 after hepatectomy, compared with the preoperative levels. Meanwhile, significantly decreased ShVO2 levels were observed at days 1 and 3, and the ShVO2 levels were significantly correlated with the HVO2. Furthermore, the decreased ShVO2 levels were synchronized with the increased DNA synthesis in the remnant liver. Energy charge levels were also significantly decreased at day 1 after hepatectomy. These results suggest that the regenerating liver demands an increased amount of oxygen for mitochondrial oxidative phosphorylation to restore hepatic energy charge. In conclusion, the ShVO2 after hepatectomy may reflect oxygen metabolic status in the remnant liver and could be useful for estimating liver regeneration.

Animals↗

Early-enhancing nonneoplastic lesions on gadolinium-enhanced magnetic resonance imaging of the liver following partial hepatectomy.

PURPOSE: To assess the frequency, imaging findings, and significance of early-enhancing nonneoplastic (EN) lesions with gadolinium-enhanced magnetic resonance imaging (MRI) of the liver following partial hepatectomy. MATERIALS AND METHODS: We retrospectively reviewed MR images after partial hepatectomy in 30 patients. Postoperative MRI was performed in 1-12 months (mean, 3.7 months) after partial hepatectomy. We defined the EN lesion as a lesion that was ill defined; irregular, wedge shaped, or serpiginous; located along the liver edge; not visible on unenhanced MR images; did not appear hypointense on portal venous- or equilibrium-phase images; or a combination of those imaging findings. RESULTS: A total of 39 EN lesions (size range, 5-60 mm; mean, 25.2 mm) in 19 patients and 17 recurrent tumors (size range, 5-50 mm; mean, 16.8 mm) in 10 patients newly appeared after partial hepatectomy. The EN lesions were diagnosed as pseudolesions by the second postoperative follow-up MRI in 17 patients or contrast-enhanced computed tomography (CT) in two. A total of 13 EN lesions (33%) were located along the liver edge and 20 (51%) were adjacent to the resected area. The shape was circular in 11 (28%), oval in three (8%), irregular in 11 (28%), wedge shaped in five (13%), and serpiginous in nine (23%). No EN lesion showed hypointensity on gadolinium-enhanced portal venous-phase or equilibrium-phase images. A total of 14 EN lesions (36%) showed slight hyperintensity on T2-weighted images. The confidence levels for malignancy probability assigned by blinded radiologists were lower with EN lesions than with recurrent tumors (P < 0.001). CONCLUSION: EN lesions are frequently seen in MRI following partial hepatectomy, and occasionally are slightly hyperintense on T2-weighted images, mimicking malignant tumors. However, most EN lesions can be correctly diagnosed with MRI findings.

Aged↗

The trans-metastasis hepatectomy (through metastases previously ablated with radiofrequency): results of a 13-case study of colorectal cancer.

BACKGROUND: Curative trans-metastasis liver resection immediately following radiofrequency (RF) destruction is a new technique that enables the proposition of a curative approach to patients with bilateral, unresectable liver metastases (LM), when the only possible future hepatectomy plane passes through a LM. Firstly, the ill-sited LM, which is located in the only feasible future hepatectomy plane, is ablated using RF; the hepatectomy is then performed through this ablated LM. AIM: The aim of this study is to report the feasibility and efficacy of this new approach, known as post-RF-trans-metastasis-hepatectomy (PRFTMH). MATERIALS AND METHODS: Thirteen patients with colorectal primary cancer were treated with PRFTMPH between January 2000 and May 2004. The mean number of LMs per patient was 10.7. Preoperative hypertrophy of the future remaining liver was achieved by selective portal vein embolization in eight patients. RESULTS: The mortality rate was 7.6% (one death), and morbidity was 24%. No local recurrence was observed at the PRTMPH site after a mean follow-up of 19.4 months (range: 47-10), demonstrating the efficacy of this technique. All patients, except those who died postoperatively, are currently alive; the median survival has not yet been attained after a mean follow-up of 19.4 months. CONCLUSION: TMPRFH is a new and safe technique, combining RF ablation and trans-RF-hepatectomy, which makes it possible to propose a curative approach in certain patients with non-resectable bilateral LMs.

Adult↗

Favorable indications for hepatectomy in patients with liver metastasis from gastric cancer.

BACKGROUND: The prognosis of patients with liver metastasis from gastric cancer (LMGC) is dismal. The purpose of this study was to review our recent outcomes of hepatectomy for LMGC and to determine the suitable candidates for surgery. STUDY DESIGN: The outcomes of 37 patients with LMGC who underwent hepatectomy between 1990 and 2005 were assessed. No extrahepatic distant metastasis and feasibility of macroscopic curative resection were requisite indications for surgery. The prognostic values of clinicopathological factors were assessed by univariate and multivariate analyses. RESULTS: There was no in-hospital mortality. The median survival time and overall 5-year survival rate after hepatectomy of the patients with LMGC were 31 months and 11%, respectively. Intrahepatic recurrence following hepatectomy was found in 23 patients (62%). Variables independently associated with poor survival were bilobar metastasis (P = 0.002, CI = 1.9-16.3) and a maximum tumor diameter of >or= 4 cm (P = 0.006, CI = 1.4-7.7). The depth of the primary tumor and the timing of metastasis were not associated with survival. CONCLUSIONS: Surgical resection for LMGC may be indicated in patients with unilobar metastasis and/or tumors less than 4 cm in diameter. Synchronous metastasis is not a contraindication for hepatectomy.

Adenocarcinoma↗

Modifications of intracellular calcium release channels and calcium mobilization following 70% hepatectomy.

The aim of this study was to investigate the properties of ryanodine and IP3 receptors in regenerating liver following 70% hepatectomy, and to evaluate the hepatic Ca2+ distribution and mobilization during this process. Specific [3H]ryanodine and [3H]IP3 binding to hepatic smooth endoplasmic reticulum membranes, as well as subcellular Ca2+ determination by atomic absorption flame photometry and Ca2+ mobilization by INDO-1 AM spectrofluorescence in hepatocytes, was performed in regenerating livers after surgical 70% hepatectomy. Incorporation of 14C amino acids into proteins and of 32P into phospholipids was done in subcellular fractions. Ryanodine receptor Kd presented a dramatic increase after 12 h of surgery and remained high up to 2 days of treatment. IP3 receptor Bmax showed a significant augmentation starting at 6 h after hepatectomy and returning to normal values after 1 week. Cytosolic total calcium content decreased from 12 h until 4 days after hepatectomy whereas the microsomal and mitochondrial total calcium increased at 1 and 2-4 days of liver regeneration, which coincided with the differential turnover of proteins and phospholipids in these fractions. ATP-induced Ca2+ transients in hepatocytes of 24-h-hepatectomized rats confirmed the altered sensitivity of the ryanodine receptor toward its ligand, since 10 times more ryanodine was necessary to alter the ATP-induced Ca2+ transient. The data support the notion that the calcium release channels are targets of mechanisms of metabolic control during the proliferative response following 70% hepatectomy and might be part of the modified intracellular Ca2+ dynamics during liver regeneration.

Animals↗

Altered fluidity of liver plasma membranes following partial hepatectomy in rats.

The fluidity of liver plasma membranes was assessed during regeneration following partial hepatectomy in rats. Fluorescence polarization was measured using 1,6-diphenyl-1,3,5-hexatriene to evaluate the fluidity of liver plasma membranes. The fluorescence polarization value of liver plasma membranes of control rats was 0.189 +/- 0.005 (mean +/- SEM). The fluorescence polarization values decreased initially after a 70% hepatectomy [0.176 +/- 0.003 at 3 hr and 0.174 +/- 0.004 at 6 hr (P < 0.01)] at 3 and 6 hours, but then recovered to preoperative levels (0.181 +/- 0.004, 0.189 +/- 0.004, 0.189 +/- 0.003, 0.193 +/- 0.003, 0.200 +/- 0.002, 0.208 +/- 0.007, and 0.190 +/- 0.003 at 12, 24, 36, 48, 72, 96 hr, and 7 days, respectively). Flow cytometric analysis using anti-bromodeoxyuridine (BrdU) monoclonal antibody was used to investigate the cell kinetics of the regenerating liver after 70% hepatectomy. The proportion of S-phase incorporating BrdU was not increased at 6 or 12 hr, but it then increased to peak of 27.9 +/- 1.9% at 24 hr. Subsequently, at 48, 72, and 168 hr, the proportion decreased to 8.5 +/- 0.6, 5.9 +/- 0.3, and 1.0 +/- 0.1%, respectively. The ratio of phospholipid to cholesterol contents of liver plasma membranes following partial hepatectomy did not significantly change in spite of markedly altered membrane fluidity. Thus, the alteration of membrane function occurs in conjunction with the initiation of the regeneration process following partial hepatectomy. It is suggested that the alteration of membrane fluidity plays an important role in the homeostatic response for cell proliferation.

Animals↗

Duration of liver ischemia and hepatic regeneration after hepatectomy in rats.

Since an occlusion of the vascular inflow to the liver is a useful technique in liver surgery, a relation between ischemia and regeneration in the liver is particularly important. The purpose of this study was to evaluate the effect of ischemic duration on liver regeneration after massive hepatectomy. Animals were subjected to segmental liver ischemia. After 30, 60, or 90 min, nonischemic liver lobes were resected (70% hepatectomy). Hepatectomy without prior liver ischemia was performed in the control group. On the 1st, 3rd, 5th, and 7th days following hepatectomy, a BrdU labeling index was calculated as a marker of liver regeneration. AST, ALT, and liver adeninenucleotides were also measured. Although 30 min of liver ischemia resulted in higher peak AST and ALT levels, liver regeneration and ATP levels were significantly higher than those in control animals. Ninety minutes of liver ischemia resulted in significantly lower liver regeneration and ATP levels compared with the other treatment paradigms. Liver regeneration and ATP levels were almost identical to those in control animals, in rats with 60 min of ischemia preceding hepatectomy. We conclude that livers regenerative capacities can tolerate significant ischemia and that relatively brief periods of ischemia can even accelerate liver regeneration.

Adenosine Triphosphate↗

Effect of glutamine supplement and hepatectomy on DNA and protein synthesis in the remnant liver.

One of the physiological roles of glutamine is as a precursor for DNA synthesis. The aims of this study were to determine (1) whether glutamine-supplemented total parenteral nutrition (TPN) enhanced DNA and protein synthesis in the liver and (2) whether glutamine uptake was increased following partial hepatectomy in rats. Male Donryu rats (n = 59; body weight, 250-275 g) were randomized into four groups: (1) sham operation + standard TPN solution (C-STPN); (2) C + glutamine-supplemented TPN (C-GTPN); (3) 70% partial hepatectomy + STPN (H-STPN); (4) partial hepatectomy + GTPN (H-GTPN). On Day 0, rats underwent either a sham operation or 70% partial hepatectomy and concomitantly were catheterized in the jugular vein. TPN was begun immediately after the surgery. GTPN was isocaloric and isonitrogenous with STPN and 25% of total nitrogen was given as glutamine. On Day 2, the animals were sacrificed after either a continuous infusion of 1-14C-leucine or a bolus i.v. injection of bromodeoxyuridine. The rate of hepatic regeneration was enhanced with glutamine supplementation (H-STPN, 60.8 +/- 1.6% vs H-GTPN, 66.3 +/- 2.0, P < 0.05) due to an increase in protein synthesis in the liver (H-STPN, 134.0 +/- 10.3%/day vs H-GTPN, 160.9 +/- 6.9, P < 0.05) and DNA synthesis in hepatocytes (H-STPN, 23.1 +/- 2.5% vs H-GTPN, 31.4 +/- 2.9, P < 0.05). The uptake of glutamine by the liver was increased following hepatectomy with GTPN supplementation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Evaluation of functional recovery of regenerating rat liver after partial hepatectomy using 31P-NMR spectroscopy.

Using 31P-NMR spectroscopy, we studied the process of the functional recovery of the regenerating rat liver at 1-5 weeks after a 65% partial hepatectomy from the viewpoint of phosphate metabolism. Portal vein clamping (20 min) or fructose administration (250 mg/kg body weight) was performed to temporarily reduce adenosine triphosphate (ATP) content in the remnant liver. Changes in ATP level were observed for 60 min after declamping the portal vein or after fructose administration. Significant differences in the increased ATP levels after declamping the portal vein or after fructose administration were observed in each hepatectomized group. Until 3 weeks after hepatectomy, ATP levels during 60 min after declamping the portal vein or after fructose administration were significantly lower than those in the nonresected control rats. However, the increase in ATP in the 4-week group was almost identical to the increase in the control group throughout the 60 min. Remnant liver weight already returned to the nonresected control level 1 week after hepatectomy, and remained constant thereafter. On the other hand, the final ATP levels 60 min after declamping the portal vein or after fructose administration returned to the nonresected control level only after 4 weeks following hepatectomy. These results demonstrate that from the viewpoint of ATP synthesis, functional recovery of the regenerating liver to normal can be observed within 4 weeks after partial hepatectomy.

Adenosine Triphosphate↗

Experimental study on the bilirubin metabolism after major hepatectomy: alterations in the proportions of bile bilirubin subfractions.

Bilirubin metabolism after major hepatectomy was investigated experimentally using rats. After a 70% and an 80% hepatectomy, proportions of bilirubin diglucuronide (BDG) decreased, and reversely, those of bilirubin monoglucuronide (BMG) increased. These changes were even more remarkable after an 80% hepatectomy. Parallel to the decrease in the proportions of BDG, the concentrations of uridine diphosphoglucuronic acid (UDP-GA) in the remnant liver decreased, and there was a significant correlation between the changes in BDG and UDP-GA. Although UDP-glucuronyltransferase (UDP-GT) activity and energy charge of the remnant liver also decreased after surgery, these decreases were mild and returned to the control level earlier than BDG. And there was no significant correlation between the changes in BDG and those in UDP-GT activity and energy charge. In this study, the decrease of the proportions of BDG in the bile juice was long term after partial hepatectomy and the period of the decrease became longer according to the augmentation of the volume of the hepatectomized liver. We clarified that the process of the UDP-GA production was inhibited after hepatectomy and the decrease of the proportions of BDG was derived from a deficiency of substrate of the glucuronidation, UDP-GA.

Animals↗

Regenerative capacities of normal and cirrhotic livers following 70% hepatectomy in rats and the effect of alpha-tocopherol on cirrhotic regeneration.

BACKGROUND: The regeneration of normal and cirrhotic liver has been very well demonstrated after partial hepatectomy; although the tissue regenerated by cirrhotic liver is also cirrhotic. The structural differences of the regenerated tissues between normal and cirrhotic livers may also indicate different regeneration capacities. The objective of this study was to compare the regeneration capacities of normal and cirrhotic livers by bromodeoxyuridine (BrdU) incorporation and proliferating cell nuclear antigen (PCNA) labeling indices in replicating nuclei and mitotic figures in cells in partially hepatectomized normal and cirrhotic rats and to study the effect of alpha-tocopherol on cirrhotic liver regeneration. METHODS: Five groups of adult Wistar rats comprised normal livers, cirrhotic livers, regenerated normal livers, regenerated cirrhotic livers, and alpha-tocopherol-treated regenerated cirrhotic livers. Cirrhosis was induced by intragastric administration of carbon tetrachloride and phenobarbital in the drinking water of the rats. Liver regeneration capacities in normal and cirrhotic rats and following partial hepatectomy in normal and cirrhotic rats and cirrhotic rats that were administered alpha-tocopherol were evaluated through BrdU incorporation, PCNA labeling, and mitotic indices. RESULTS: BrdU and PCNA labeling and mitotic indices were zero for normal rats and 4.3 +/- 3.5, 6.5 +/- 5, and 2.5 +/- 1.5 for cirrhotic rats, respectively. The values after partial hepatectomy in normal and cirrhotic rats were 46.2 +/- 8.7 and 27.8 +/- 7.5 for BrdU labeling, 83.7 +/- 6.5 and 51.3 +/- 6.8 for PCNA labeling, and 31.8 +/- 4.2 and 18.6 +/- 3.4 for mitotic index, respectively. For the fifth group comprising cirrhotic rats that were administered alpha-tocopherol and had undergone partial hepatectomy, BrdU incorporation, PCNA labeling, and mitotic indices were 37.5 +/- 6.3, 76.5 +/- 6.2, and 27.2 +/- 4.2, respectively. When the cirrhotic liver regeneration group was compared with the normal liver regeneration group, rates of liver regeneration in the cirrhotic group were significantly depressed (P < 0.01). Although the BrdU incorporation and PCNA labeling indices of the alpha-tocopherol-administered cirrhotic liver regeneration group indicated significantly lower rates of liver regeneration when compared with the normal liver regeneration group (P < 0.05), the liver regeneration rates of the alpha-tocopherol-administered cirrhotic group were also significantly higher than those of the cirrhotic liver regeneration group that was not administered alpha-tocopherol (P < 0.01). CONCLUSIONS: Cirrhotic livers revealed a significantly depressed capacity for regeneration following partial hepatectomy. alpha-Tocopherol administration seemed to improve the rates of regeneration in cirrhotic rats with respect to the BrdU incorporation, PCNA labeling, and mitotic indices.

Animals↗

Prognostic implications of the response of arterial ketone body ratio and insulin secretion to glucose load in major hepatectomy.

Impaired glucose tolerance is a serious obstacle to major hepatic resection. To assess the predictability of surgical risk in major hepatectomy for patients with chronic liver diseases from the viewpoint of glucose metabolism, we evaluated the insulinogenic index (II) and redox tolerance index (RTI) in 48 patients who underwent major hepatectomy at our university hospital due to hepatocellular carcinoma. Patients with low II and low RTI fell into the high risk group. Based on this finding, the Z score was developed as an index of patient risk for major hepatectomy: Z = 3.11 x [II] + 1.43 x [RTI] - 2.27. When the Z score was negative, mortality reached 33.3%, but when it was positive the mortality was only 3.2%. Intraportal insulin supplementation after hepatectomy to patients with a negative Z score could reduce mortality. Preoperative evaluation of surgical risk by Z score seems to be useful for predicting patient prognosis after hepatectomy.

Aged↗

Expression of HGF and TGF-beta 1 mRNA after partial hepatectomy in rats with liver cirrhosis.

Hepatocyte growth factor (HGF) is a potent mitogen for the maturation of hepatocytes in vitro which plays a role in liver regeneration in vivo. In addition, transforming growth factor-beta 1 (TGF-beta 1) is also a potent regulator of liver regeneration. In attempting to clarify the mechanisms related to liver regeneration after partial hepatectomy, we investigated the expression of HGF and TGF-beta 1 in rats with liver cirrhosis (LC). A rat model of LC was prepared using carbon tetrachloride (CCl4). The expression of HGF mRNA in both the LC and control groups showed a similar time-course with the highest expression seen at 18h after a 70% hepatectomy. The expression of TGF-beta 1 mRNA peaked at 18h after partial hepatectomy in the LC group and at 48h in the control group. The 5-bromo-2'-deoxyuridine (BrdU) labeling index for the LC group at 24, 48, and 72 h after partial hepatectomy was 9.2%, 5.9%, and 1.8%, while for the control group it was 7.0%, 11.7%, and 6.8%, respectively. The BrdU labeling index in the LC group was thus suppressed earlier than that in the control group. We therefore postulate that regeneration of the remnant liver in the presence of LC accelerates immediately after partial hepatectomy, but the extent of regeneration is insufficient because of an early cessation due to an early expression of TGF-beta 1.

Animals↗

Lateral hypothalamic lesions facilitate hepatic regeneration after partial hepatectomy in rats.

It has been reported that ventromedial hypothalamic lesions facilitate hepatic regeneration through the hepatic vagal nerve after partial hepatectomy. However, whether the lateral area of the hypothalamus is involved in liver regeneration after partial hepatectomy is unknown. To determine the role of the lateral hypothalamic area in this phenomenon, we studied hepatic DNA synthesis during liver regeneration after partial hepatectomy with bilateral lesions of the area. Lesioning of the lateral hypothalamus accelerated the increase in hepatic DNA synthesis and raised the peak level of [methyl-3H]thymidine incorporation after partial hepatectomy. These effects of hypothalamic lesioning were inhibited by combined hepatic vagotomy and sympathectomy. Our results demonstrate that lesioning of the lateral hypothalamus promotes hepatic regeneration through the autonomic nervous system after partial hepatectomy and suggest that the lateral hypothalamic area is involved in liver regeneration through neural mediation.

Animals↗

Estimation of remnant liver function before hepatectomy by means of technetium-99m-diethylenetriamine-pentaacetic acid galactosyl human albumin.

To improve the results of hepatectomy in cirrhotic patients, the likely reserve function of the liver was evaluated before surgery. Asialoglycoprotein receptor (ASGP-R) is a hepatic cell surface receptor specific for galactose-terminated glycoproteins. Technetium-99m-diethylene triamine pentaacetic acid-galactosyl human serum albumin (99mTc-GSA) is a newly developed analog ligand to ASPG-R. The probable functional reserve of the remnant liver after hepatectomy was estimated preoperatively as the hepatic binding protein (HBP) concentration specific for ASGP-R on the hepatocellular membrane of the remnant liver. This estimate was based on the effective liver volume rate, obtained by the uptake of 99mTc-GSA. In all, 3 normal volunteers, 3 patients with chronic hepatitis (CH), 9 patients with liver cirrhosis (LC), 2 patients with hepatic cystadenoma, 3 patients with hepatocellular carcinoma (HCC) associated with CH, and 21 HCC patients with LC were studied. The mean value +/- SD obtained for HBP in normal volunteers (three cases) and in patients with mild (four cases), moderate (two cases), and severe liver damage (five cases) were 0.74 +/- 0.03 microM, 0.43 +/- 0.042 microM, 0.31 +/- 0.05 microM, and 0.20 +/- 0.05 microM, respectively. Most of the cases in which the preoperative HBP of the remnant liver was above 0.22 microM had a good postoperative course irrespective of the type of hepatectomy. On the other hand, in subjects with a remnant liver HBP of between 0.22 and 0.11 microM, postoperative severe liver dysfunction occurred in about 50% of cases. In all cases with a remnant liver HBP below 0.1 microM, the prognosis was very poor, indicating that hepatectomy should be avoided. The HBP concentration detected by the 99mTc-GSA study is a very sensitive indicator of changes in the hepatic functional reserve, and the HBP value for the functional reserve of the remnant liver is extremely useful for estimating the liver function before and after hepatectomy.

Adult↗

Pathophysiology of dogs after 84% hepatectomy with emphasis on prostaglandin metabolites and the effect of a thromboxane A2 synthesis inhibitor and a prostaglandin I2 analog.

The pathophysiological conditions following 84% hepatectomy were examined in terms of the changes in thromboxane A2 (TxA2) and prostaglandin I2 (PGI2) in a canine model. OKY-046, a TxA2 inhibitor, and OP-2507, a PGI2 analog, were administered to evaluate the possibility of extending hepatic resection. The 2-week survival rate following 84% hepatectomy significantly improved after the administration of OKY-046 and OP-2507, from 12.5% to 58.3% and 75.0%, respectively. Furthermore, OP-2507 significantly improved impaired hepatocyte and sinusoidal endothelial cell function after 84% hepatectomy, resulting in a satisfactory recovery to the preoperative levels. Within 24 h after 84% hepatectomy, the plasma levels of thromboxane B2 (TxB2) increased significantly, and the 6-keto-prostaglandin F1 alpha (6-KF) levels became slightly elevated. OKY-046 and OP-2507 decreased TxB2 and increased 6-KF in the plasma, resulting in the maintenance of sufficient blood flow in the portal vein and hepatic tissue and the mitigation of microcirculatory disorders. Moreover, the cytoprotective effects of the two drugs inhibited functional impairment of the residual liver. In conclusion, abnormal prostaglandin metabolites were produced after 84% hepatectomy, being involved in residual liver disorders. However, the administration of either an inhibitor of TxA2 synthesis or a PGI2 analog ameliorated the functional impairment of the residual liver, which suggests their potential value for extending the resectability of the liver from what is presently feasible.

6-Ketoprostaglandin F1 alpha↗

The enhancement of tumor growth after partial hepatectomy and the effect of sera obtained from hepatectomized rats on tumor cell growth.

In the process of liver regeneration, the participation of various types of growth stimulators and changes in immune responses have been reported. Here, we examined the growth of subcutaneously transplanted AH130 cells and Walker 256 cells after partial hepatectomy. In the case of tumor cells being transplanted on the same day as partial hepatectomy, the increase in tumor size in hepatectomized rats was significantly greater compared with that in non-treated rats or in those having undergone a simple laparotomy. When the transplantation of tumor cells was done on the 7th day after partial hepatectomy, however, the increase was less marked. We also examined the effect of serum obtained from rats after partial hepatectomy on the in vitro growth of these tumor cells. Growth enhancement was observed with medium containing serum drawn from rats 1 to 4 days after partial hepatectomy. These results suggest that the growth of tumor cells was stimulated during liver regeneration and that some humoral factors participated in the process. Furthermore, as the conditions of the in vitro method appear to mimic those of the in vivo method, the in vitro approach should be very useful for analysis of the factors responsible.

Animals↗