the effects of pentoxifylline on liver regeneration after portal vein ligation in rats

BAS IC STUDIES

The e¡ects of pentoxifylline on liver regenerationafter portal veinligation in ratsUzer Kucuktulu1, Etem Alhan1, Yavuz Tekelioglu2 and Aysel Ozekin3

1 Department of General Surgery, Karadeniz Technical University, Trabzon, Turkey

2 Department of Histology and Embriology, Karadeniz Technical University, Trabzon, Turkey

3 Department of Biochemistry, Karadeniz Technical University, Trabzon, Turkey

Keywords

liver regeneration – pentoxifylline – portal

vein ligation

Correspondence

Dr. Uzer kucuktulu, Department of General

Surgery, Karadeniz Technical University,

Trabzon, Turkey

e-mail: [email protected]

Received 23 August 2006

accepted 6 November 2006

DOI:10.1111/j.1478-3231.2006.01419.x

AbstractAim: To determine the effects of pentoxifylline, a methyl xanthine derivative on

hepatic cell production of uninterferred lobe after portal vein branch ligation.

Methods: Sixty-six rats were randomly allocated into 9 groups with 8 rats in PVL

groups and 6 rats in sham operation groups. The portal branches of the median

and the lateral liver lobes, corresponding to approximately 70% of the liver voluma

were ligated in the PVL groups. The control group received 0.9% NaCl solution.

The rats in the treatment groups received pentoxypilline at the dose of 50 mg/kg/

dy. After 1,2,4 days of portal vein ligation in both PVL and PVNL lobes the levels of

adenine nucleotides were determined and flowcytometric analysis of cell cycles

were performed. Results: On the first day of portal branch ligation energy charge

was significantly lower, in pentoxifylline treated group comparing to pentoxfylline

untreated group, both in PVL and PVNL lobes (Po 0.05). Proliferative indexes

were 0.38 and 0.29 in pentoxifylline treated and pentoxifylline untreated PVNL

lobes respectively (Po 0.05). Conclusion: Pentoxifylline treatment resulted in an

increase of percentage of calls entering mitosis phase on the first day after PVL,

somehow accelerating the regenaration process.

Extended hepatic resection is a surgical means forselected patients with hilar cholangiocarcinoma (1),advanced gallbladder cancer (2) and metastatic livercancer (3). However, liver surgeons face a dilemmathat wide hepatic resections while achieving cure canleave insufficient remnant liver function (4).

Preoperative embolization of portal branch thatsupply the segment or lobe of the liver to be resectedis a clinical manipulation to increase the remainingliver volume and functional capacity (5–7). In animalmodels it has been shown that the portal vein ligationleads to progressive atrophy of the liver lobe deprivedof portal blood, whereas hypertrophy occurs in theuninterferred lobe in rabbits, dogs and rats (8–10).

Pentoxifylline, a methyl xanthine derivative, exhibitsbeneficial biologic effects in sepsis, haemorrhage ornonhaemorrhagic ischaemia in various organs(11–13). In the liver, pentoxifylline has been shown toincrease hepatic surface oxygenation (14) and restorehepatocellular function after haemorrhage (15) orischaemia (16, 17). The proposed mechanism ofactions includes improvement of cardiac output andmicrovascular circulation (18), hemorrheologic effects

on leucocytes, erythrocytes and platelets (19, 20) andvasodilatation (21).

This study was designed to examine the effects ofpentoxifylline on hepatic cell proliferation of uninter-ferred lobe after portal vein branch ligation (PVL).

Materials and methods

Sixty-six male Sprague–Dawley rats (250–300 g) wereused in the experiment. All rats were kept in tempera-ture-controlled room with a 12 h light–dark cycle. Theanimals were given a standard rat chow and fastedovernight before the experiment with free access towater. The experimental protocols were approved bythe Animal Care and Use Committee of the KaradenizTechnical University, Trabzon, Turkey. The rats wererandomly allocated into nine groups with eight rats inPVL groups and six rats in sham operation groups.

Anaesthesia was induced with vaporized ether andmaintained by an intraperitoneal injection of keta-mine (40 mg/kg, Ketalar; Parke–Davis and Eczacıbas, ı,Istanbul). On the day before the experiment, the rightinternal jugular vein was cannulated using soft

Liver International (2007)274 c� 2007 The Authors. Journal compilation c� 2007 Blackwell Munksgaard

Liver International ISSN 1478-3223

polyethylene tubing (Silastic, inner diameter 0.58 mm;Portex, Smiths Medical, London, UK, EE 1594). Thecatheter was tunnelled to the suprascapular area.

The next day, the animals were transferred to thelaboratory and allowed to adapt to the new environ-ment for 30 min with noise and visual stimuli kept to aminimum. For abdominal manipulations, the animalswere given a short acting (ketamine 50 mg/kg) anaes-thesia and the abdomen was opened by a midlineincision.

The portal branches of the median and the lateralliver lobes, corresponding to approximately 70% of theliver volume, were ligated under an operation micro-scope (� 5) in the PVL groups. In the sham-operatedgroup, portal branches were similarly manipulated afterlaparotomy but not ligated. The control group received0.9% NaCl solution continuously, at a rate of 2 ml/hthrough the internal jugular vein catheter. The rats inthe treatment groups received pentoxypilline at the doseof 50 mg/kg/day in 0.9% NaCl solution that was infusedcontinuously at the rate of 2 ml/h.

After 1, 2 and 4 days of portal vein ligation undersimilar anesthesia, small liver tissues (o 100 mg) werecut with cooled scissors from both PVNL and PVL

liver lobes of the corresponding groups. The tissueswere immediately frozen in liquid nitrogen for theanalysis of adenine nucleotides. The PVL and PVNLliver lobes were separately excised, weighted and usedfor flowcytometric analysis of cell cycles. All proce-dures were performed between 10:00 and 12:00 hours.The study was approved by Ethical Committee ofKaradeniz Technical University.

Analytical methods

Adenine nucleotides in the liver tissues: The frozen liversamples (o 100 mg) were lypolized overnight. Thelypolized samples weighing 10–15 mg were homoge-nized in 1 ml of 0.5 N per chloric acid. The homogenatewas centrifuged for 5 min at 10.000g at 4 1C. After theaddition of 0.05 ml of 3 M potassium hydroxide to0.5 ml of supernatant, the sample was recentrifuged for10 min under the same condition. In the microfilteredsupernatant, adenine nucleotides were determined asdescribed (22). Total adenine nucleotide (TAN; ex-pressed in mmol/g dry liver) and energy charge (EC)were calculated as follows: TAN = ATP1ADP1AMP;EC = (ATP11/2ADP)/(ATP1ADP1AMP) (23).

Table 1. Distribution of cells in flowcytometric cell cycle analysis

Days after PVL Groups

Cell cycle

Lw/Bw% G0 G1% S% G2 M% PI

1 Sham 4.2� 0.2 94.42� 3.64 3.22� 0.55 2.36� 0.41 0.05PVL onlyPVL lobes 2.9� 0.4 94.58� 4.12 3.14� 0.34 2.28� 0.42 0.05PVNL lobes 1.4� 0.1 70.98� 3.48� 21.35� 1.38� 7.67� 1.58� 0.29�

PVL1pentxPVL lobes 2.7� 0.3 94.33� 3.27 3.45� 0.28 2.22� 0.46 0.05PVNL lobes 1.7� 0.6 61.39� 2.56� 12.47� 1.29�,�� 26.14� 3.75�,�� 0.38�,��

2 Sham 3.9� 0.1 93.94� 2.98 2.87� 0.42 3.19� 0.83 0.06PVL onlyPVL lobes 2.1� 0.3 94.89� 2.12 2.77� 0.73 2.34� 0.22 0.05PVNL lobes 1.8� 0.1 59.99� 3.52� 7.63� 1.48� 32.38� 3.96� 0.40�

PVL1pentxPVL lobes 2.0� 0.4 93.29� 4.03 2.95� 0.57 3.76� 1.28 0.06PVNL lobes 1.7� 0.3 60.35� 5.22� 8.53� 1.78� 31.12� 2.67� 0.39�

4 Sham 4.1� 0.3 93.73� 3.45 2.50� 0.23 3.77� 0.32 0.06PVL onlyPVL lobes 1.2� 0.2 93.85� 2.86 2.47� 0.41 3.68� 1.06 0.06PVNL lobes 3.0� 0.2 62.22� 3.15 � 4.32� 1.24�� 33.46� 4.33� 0.37�

PVL1pentxPVL lobes 1.2� 0.3 93.89� 2.57 2.66� 0.36 3.45� 1.07 0.06PVNL lobes 3.2� 0.4 63.39� 4.32� 3.64� 0.45�� 32.97� 3.46� 0.36�

�Po 0.01 vs sham operated group on the same day.��Po 0.01 vs pentoxifylline nontreated PVNL lobes on the same day.��Po 0.05 vs sham operated groups on the same day.��Po 0.05 vs pentoxifylline nontreated PVNL lobes on the same day.

PI, proliferation index; PVL, portal vein branch ligation.

Liver International (2007)c� 2007 The Authors. Journal compilation c� 2007 Blackwell Munksgaard 275

Kucuktulu et al. Pentoxifylline on liver regeneration in rats

Flow cytometric analysis of the cell cycle

The specimens for flow cytometry were preparedimmediately after the removal of liver. The tissue wasmechanically minced and then filtered through a 200 mmesh filter. After staining with propidium iodide(DNA-Prep Coulter Reagents Kit, Coulter Coopera-tion, Fullerton, CA, USA), flow cytometry was per-formed under 488–600 nm argon ion laser (CoulterEpics Elite ESP, Coulter Cooperation). A total of2� 104 cells were examined for each sample.

Cell cycle parameters were analysed by DNA cellcycle analysis software (Multicycle AV, PhoneixFlow Systems, San Diego), and the percentages of cellsin G0, G1, S, G2 M phases of the cell cycle werecalculated and the cell proliferation index (PI) wasexpressed as the percentage of cells in S plus G2Mphases.

Results

The weights changes of PVL and PVNL lobes in bothpentoxypillin treated and control groups are shown inTable 1. On days 2 and 4, the ratio of PVNL lobes tobody weight increased reaching up to 70% of wholeliver weight by day 4. PVL lobe/body weight ratio

decreased concomitantly and, as a result, total liverweight/body weight ratio remained essentially con-stant and no significant difference was found betweentwo groups throughout the experiment.

The changes in concentration of AMP, ADP, ATPand TAN are shown in Table 2. In PVNL groups theconcentration of TAN remained constant throughoutthe experiment. But in PVL groups TAN concentra-tions were decreased significantly on day 4. TANconcentrations were 14.30� 0.28 and 14.30� 0.28 inpentoxyphilline treated and non-treated groups, re-spectively. Pentoxyphyline administration resulted inno significant difference as far as TAN concentrationswere concerned. On the first day after PVL, AMP andADP levels increased and ATP levels decreased in bothPVL and PVNL lobes in both pentoxyphilline-treatedand non-treated groups comparing with sham-oper-ated groups. PVL and PVNL lobes showed no signifi-cant difference within the same group. ATP levels were4.53� 0.47 in pentoxyphilline-treated PVNL lobeswhile they were 6.23� 0.34 in pentoxyphilline non-treated lobes. In PVL lobes ATP levels were 4.48� 0.58and 6.60� 0.42 in pentoxyphilline treated and non-treated groups, respectively. The differences were sta-tistically significant (Po 0.05).

Table 2. Adenine nucleotides in liver tissue

Days after PVL Groups

Concentration, mmol/g of wet liver� SD

AMP ADP ATP TAN EC

1 Sham 2.93� 0.29 5.31� 0.33 8.91� 0.39 17.15� 0.32 0.67PVL onlyPVL lobes 4.88� 0.33� 6.20� 0.31� 6.60� 0.42� 17.68� 0.35 0.54�

PVNL lobes 4.20� 0.20� 6.83� 0.24� 6.23� 0.34� 17.26� 0.26 0.55�

PVL1pentxPVL lobes 5.23� 0.51� 7.53� 0.38� 4.48� 0.58�,�� 17.24� 0.47 0.47�,��

PVNL lobes 5.19� 0.36�,�� 7.50� 0.35� 4.53� 0.47� 17.22� 0.41 0.48�,��

2 Sham 3.35� 0.32 5.50� 0.38 8.41� 0.73 17.26� 0.93 0.64PVL onlyPVL lobes 3.82� 0.37 6.53� 0.47 7.38� 0.66 17.73� 0.53 0.60VNL lobes 3.98� 0.34 6.51� 0.53 7.25� 0.47 17.74� 0.48 0.59PVL1pentxPVL lobes 3.76� 0.32 6.49� 0.53 7.42� 0.44 17.67� 0.47 0.60PVNL lobes 4.04� 0.28 6.58� 0.46 7.18� 0.31 17.80� 0.38 0.58

4 Sham 3.37� 0.32 5.85� 0.24 7.78� 0.41 17.00� 1.12 0.62PVL onlyPVL lobes 3.20� 0.42 4.35� 0.38 6.71� 0.55 14.26� 0.44� 0.62PVNL lobes 3.54� 0.11 6.43� 0.18 7.46� 0.52 17.43� 0.31 0.61PVL1pentxPVL lobes 3.25� 0.31 4.39� 0.23 6.66� 0.27 14.30� 0.28� 0.61PVNL lobes 3.61� 0.44 6.38� 0.24 7.48� 0.45 17.47� 0.39 0.61

�Po 0.05 vs sham operated group on the same day.��Po 0.05 vs pentoxifylline nontreated PVL lobes.��Po 0.05 vs pentoxifylline nontreated PVNL lobes.

PVL, portal vein branch ligation; TAN, Total adenine nucleotide; EC, Energy charge.


Pentoxifylline on liver regeneration in rats Kucuktulu et al.

On day one after PVL the percentage of cells inS phase were 12.47� 1.29 and 21.35� 1.38 in pentox-yphilline-treated and nontreated groups respectively.The percentage of cells in G2 M phase were26.14� 3.75 in pentoxyphilline-treated group and7.67� 1.58 in pentoxyphilline-non-treated groups.The difference between the groups were statisticallysignificant (Po 0.01). PI was significantly higherin PVNL lobes of pentoxyphilline-treated groups (0.38vs 0.29; Po 0.05). On the second and fourth days afterPVL the cell distribution in mitotic cycle weresimilar in both pentoxyphilline-treated and non-treatedgroups.

Discussion

In current surgical practice, major technical complica-tions and fatal liver failure after hepatic resections arerare. However, complications related to insufficientfunction of the remaining liver still contributes mor-bidity and extended hospital stay after major hepaticresections (24–27).

Rous and Larimore observed in 1920 that portalvein ligation in rabbits leads to atrophy of the ipsilat-eral hepatic lobe and hypertrophy of the contra laterallobe (8). In humans observation of same results afterportal vein ligation (28) or occlusion resulting fromtumour invasion (29) provided the stimulus for liverregeneration studies. Kinoshita et al. (30)published thefirst report demonstrating the efficacy of portal veinocclusion before resection of hepatocellular carcino-ma. Portal vein embolization (PVE) was utilized toinitiate future liver remnant hypertrophy before ex-tended resection for hilar bile duct cancer by Makuu-chi et al. (31).

Although the trigger mechanism of the liver hyper-trophy is not well understood, the most powerfulstimulus is hepatocyte growth factor (HGF), which isreleased from the hepatocytes in response to hepato-cellular injury and exerts a mitogenic effect (32–33). Inaddition to HCG, epidermal growth factor, transform-ing growth factor (TGF)-a (32), insulin (34), nora-drenalin (35) and specifically portal hormones, (32)are comitogenic signals for hepatic hypertrophy.

In our experimental design on day one after PVL,the PI values were 0.38 and 0.29 in pentoxifylline-treated and pentoxifylline-untreated PVNL lobes re-spectably. The difference was statistically significant(Po 0.05). The cell cycle analysis showed that inPVNLs 26.14% of cells were in G2 M phase whentreated with pentoxifylline, while in untreated PVNLsthe ratio of cells in G2 M phase was 7.67%. The ratio ofcells in S phase was 12.47% and 21.35% in pentoxifyl-

line-treated and untreated groups, respectively(Po 0.01). This showed that in pentoxifylline-treatedgroup the percentage of hepatocytes that completedsynthesis phase and entered mitosis phase was highercompared with pentoxifylline-untreated groups onday 1 after PVL. On days 2 and 4 after PVL, thedistribution of the cells in cell cycle was similar.Pentoxifylline treatment seems to accelerate regenera-tion process on day 1 after PVL.

Atkinson described that EC reflects the metabolicallyavailable energy pool that depends on the differencebetween the ATP-generating and ATP-utilizing reac-tions (23). It is well documented that DNA synthesisrequires hepatic energy (36) and a decline in ECprecedes the liver regeneration (37). In our experimen-tal model, on day 1 after PVL, EC was significantlylower, in pentoxifylline-treated group compared withpentoxifylline-untreated group, both in PVL andPVNL lobes (Po 0.05). It shows that pentoxifylline-treated group had more ATP-utilizing activity. Thisfinding supports increased mitotic activity in thisgroup. In PVNL lobes, TAN remained unchangedthroughout the experiment but in PVL lobes on thefourth day after PVL it decreased significantly. Onfourth day in PVL lobes atrophy was almost completeand accompanied by decrease in energy requirements.

On the 4th day after PVL the ratio of liver weight tobody weight was almost reversed in PVL and PVNLlobes and PVNL lobes reached nearly 70% of wholeliver weight. Pentoxifylline treatment had no effect onthis ratio.

Kin et al. (38)first demonstrated a significant corre-lation between the portal blood flow (PBF) velocityand the hepatic growth rate in patients after a majorhepatectomy. Goto et al. reported that in humansubjects PBF velocity approximately doubled on day 1after PVE and, despite a subsequent gradual decrease,remained significantly elevated until day 14. They alsoreported that the liver hypertrophy rate correlatedclosely with the extent of the increase in the PBFvelocity and the hypertrophy rate of nonembolizedhepatic segments after PVE is predictable from theextent of increase in the PBF velocity (39).

Pentoxifylline, a methyl xanthine derivative, exhibitsbeneficial biologic effects in sepsis, hemorrhage or non-haemorrhagic ischaemia in various organs (11–13).Pentoxifylline has been shown to increase hepatic sur-face oxygenation (14) and restore hepatocellular func-tion after hemorrhage (15) or ischaemia (16, 17). Theproposed mechanism of actions includes improvementin cardiac output and micro vascular circulation (18),hemorrheologic effects on leucocytes, erythrocytes andplatelets (19, 20) and vasodilatation (21). The reason of



acceleration of regeneration process in pentoxifylline-treated PVNL group on day one after PVL may berelated to improved hepatic microcirculation.

In conclusion, pentoxifylline treatment resulted inan increase in percentage of cells entering mitosisphase on the first day after PVL, somehow acceleratingthe regeneration process. This might be the result ofincreased microcirculation in liver after pentoxifyllinetreatment. Human studies are required to find out theeffects of pentoxifylline on liver regeneration afterportal vein embolization.

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the effects of pentoxifylline on liver regeneration after portal vein ligation in rats

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