Inhibition of 5-lipoxygenase promotes the regeneration of the liver after partial hepatectomy in...

Inhibition of 5-Lipoxygenase Promotes the Regenerationof the Liver After Partial Hepatectomy in Normal

and Icteric Rats

MASAAKI URADE, RYOHEI IZUMI, AND HIROHISA KITAGAWA

The role of leukotriene (LT) on liver regeneration tion1 and immune response2-6 by a variety of mecha-after hepatectomy is still unknown. LTB4 stagnates in nisms such as enhancement of leukocyte migration, de-the liver with obstructive jaundice, because LTB4 is ex- granulation of neutrophils, production of interleukin-creted in the bile; therefore, LTB4 may have an effect on 1, and activation of macrophages, natural killer cells,liver regeneration after hepatectomy with obstructive and cytotoxic T lymphocytes. However, the role of LTsjaundice. Release of obstructive jaundice and simultane- in liver regeneration after hepatectomy is still un-ous 70% hepatectomy was performed in rats to study known.7the effect of 5-lipoxygenase inhibitor (AA-861) on liver

LTB4 is normally metabolized in the liver and ex-regeneration. Group 1 underwent hepatectomy with ad-creted into the bile,8 so it is thought that it accumulatesministration of 0.1 mL dimethyl sulfoxide (DMSO), groupin obstructive jaundice and may possibly have an unfa-2 underwent hepatectomy with administration of AA-

861 (20 mg/kg/d) dissolved in 0.1 mL DMSO, group 3 un- vorable effect on liver regeneration after hepatectomy.derwent hepatectomy with administration of AA-861 (40 Therefore, we presume that LTs may play an importantmg/kg/d) dissolved in 0.1 mL DMSO, group 4 underwent role in liver injuries and that inhibition of 5-lipoxygen-release of obstructive jaundice and hepatectomy with ase may be beneficial for liver regeneration.administration of 0.1 mL DMSO, and group 5 underwent Hepatectomy is often performed in the presence ofrelief of obstructive jaundice and hepatectomy with ad- obstructive jaundice when patients have cancer of bileministration of AA-861 (20 mg/kg/d). DMSO or AA-861 duct at porta hepatis or gallbladder.9,10 In the presentwas administered 24 hours before, during, and 24 hours

study, the effect of a 5-lipoxygenase inhibitor on liverafter hepatectomy in each group. Whole blood LTB4 andregeneration after partial hepatectomy was evaluatedserum alanine aminotransferase (ALT), total bilirubin,in normal and icteric rats that underwent decompres-and bromodeoxyuridine labeling index (LI) were mea-

sured before and after hepatectomy. The LTB4 level in- sion of obstructive jaundice with concurrent hepatec-creased during obstructive jaundice and after hepatec- tomy.tomy. LTB4 and serum ALT levels were significantlylower after hepatectomy in the rats that were adminis- MATERIALS AND METHODStered AA-861, and a significantly higher LI was observed

Adult male Wistar rats (Sankyo Labo Service, Toyama,at 24 hours after hepatectomy in rats receiving AA-861.Japan) weighing 270 to 330 g were maintained in a constantInhibition of 5-lipoxygenase promotes liver regenera-temperature environment with a 12-hour light-dark cycletion and decreases hepatocyte injury after hepatectomyand were fed Charles River CRF-1 chow (Oriental Yeast Co.,associated with obstructive jaundice. (HEPATOLOGYTokyo, Japan) ad libitum. Before the experiment, rats were1996;23:544-548.)fasted overnight but allowed free access to water. Rats wereanesthetized by ether inhalation, followed by general anes-Arachidonic acid metabolites are produced in endo- thesia with sodium pentobarbital (3 mg/100 g body weight).

thelial cells, Kupffer cells of the hepatic sinusoids, andparenchymal hepatocytes. Leukotrienes (LTs) are me- Experiment 1tabolites of 5-lipoxygenase that accelerate inflamma-

A midline laparotomy was performed and 70% hepatec-tomy was performed by the method of Higgins and Ander-son.11 The left lateral and bilateral central lobes (correspond-Abbreviations: LT, leukotrienes; DMSO, dimethyl sulfoxide; ALT, alanine

aminotransferase; T bili, total bilirubin; BrdU, bromodeoxyuridine; LI, labeling ing to 70% of the liver) were resected, whereas the rightindex. lateral lobe, caudate lobe, caudate process, and papillary pro-

From the Department of Surgery II, School of Medicine, Kanazawa Univer- cess were left intact. The animals were divided into the fol-sity, Japan. lowing three groups.

Received January 20, 1995; September 25, 1995. Group 1. Animals were subjected to 70% hepatectomy,Address reprint requests to Masaaki Urade, M.D., Department of Surgery with administration of 0.1 mL dimethyl sulfoxide (DMSO)II, School of Medicine, Kanazawa University, 13-1, Takara-machi, Kanazawa,

subcutaneously 24 hours before, during, and 24 hours after920, Japan.hepatectomy (n Å 28).Copyright q 1996 by the American Association for the Study of Liver

Group 2. Animals were subjected to 70% hepatectomy withDiseases.0270-9139/96/2303-0020$3.00/0 subcutaneous administration of a 5-lipoxygenase inhibitor

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HEPATOLOGY Vol. 23, No. 3, 1996 URADE, IZUMI, AND KITAGAWA 545

TABLE 1. Changes of Serum T bili Levels

T bili (mg/dL)

Group 0 h 12 h 24 h 48 h

1 0 0 0 02 0 0 0 03 0 0 0 04 7.3 { 1.0* 2.2 { 2.0* 2.5 { 0.8* 0.8 { 0.6*5 6.5 { 6.1* 2.9 { 1.6* 2.1 { 0.8* 0.8 { 0.2*

NOTE. Values are mean { SD (n Å 28, per group).* P õ .01 vs. group 1.

FIG. 1. Schematic representation of operative procedures of ex- struction, and concurrent release of obstructive jaundice andperiment 2. (A) A tube is introduced into the common bile duct and 70% hepatectomy with administration of 20 mg/kg/d of AA-then ligated, creating obstructive jaundice. (B) After 1 week, the tube 861 24 hours before, during, and 24 hours after hepatectomyis cut to release the obstruction and a 70% hepatectomy is performed (n Å 28).at the same time. (C) The tube is introduced into the duodenum

Seven rats in each group were killed at 0, 12, 24, and 48constructing an internal fistula.�� , scope of resection.

hours after hepatectomy in both experiments. Immediatelybefore death, blood samples were obtained from the aorta,and livers were removed for histological investigation. The

(AA-861; 20 mg/kg/d; Takeda Pharmaceutical Co. Ltd., whole blood LTB4 level, and plasma alanine aminotransfer-Osaka, Japan) dissolved in 0.1 mL of DMSO 24 hours before, ase (ALT) and total bilirubin (T bili) levels were measured.during, and 24 hours after hepatectomy (n Å 28). All animals received humane care in compliance with the

Group 3. Animals were subjected to 70% hepatectomy with Guidelines for the Care and Use of Laboratory Animals insubcutaneous administration of 40 mg/kg/d of AA-861 dis- Takara-machi Campus of Kanazawa University.solved in 0.1 mL of DMSO 24 hours before, during, and 24 LTB4 were measured according to the method of Blair ethours after hepatectomy (n Å 28). al.12 One mL of heparinized whole blood was immediately

transferred to tubes containing 4 mL of cold ethanol and wasExperiment 2 centrifuged at 2,000g for 15 minutes. Then the supernatantwas extracted with a Sep-pak C 18 column (Amersham JapanA midline laparotomy was performed and obstructive jaun-Co., Osaka, Japan), and the LTB4 concentrations were deter-dice was produced by ligating a tube that was introduced intomined by specific radioimmunoassay, using antibodies fromthe common bile duct. The polyurethane tube (Argyle CVthe Amersham Japan Co.catheter; Japan Sherwood Co., Tokyo, Japan) with an outside

Bromodeoxyuridine (BrdU) (20 mg/kg, a thymidine ana-diameter of 0.8 mm was inserted into the common bile ductlogue) was administered intraperitoneally to the animals 1and was fixed at the porta hepatis, and its distal end washour before death. The livers were removed, fixed with forma-ligated to create obstruction. The distal end of the tube waslin, and then embedded in paraffin for sectioning. BrdU wascut to relieve the obstruction of the bile duct 1 week after, andthen visualized by immunohistochemical staining using thethe tube was introduced into the duodenum. Concurrently, aavidine-biotine-complex method. Bile duct ligation provokes70% hepatectomy was performed. In this manner, obstructiveproliferation of biliary ductal cells and mesenchymal liverjaundice relief with hepatectomy could be modelled (Fig 1).cells to some extent, but the majority of BrdU-positive cellsThe animals were divided into the two groups as follows (Figwere hepatocytes. Therefore, only BrdU-positive parenchy-2).mal liver cells were counted microscopically, but neither bili-Group 4. Animals were subjected to obstruction of commonary ductal cells nor mesenchymal cells were counted. Thebile duct, followed by release of obstructive jaundice and 70%number of cells per 1,000 hepatocytes with a deeply stainedhepatectomy with subcutaneous administration of 0.1 mLnucleus was counted and the BrdU labeling index (LI) wasDMSO 24 hours before, during, and 24 hours after hepatec-determined as an indicator of cells in the S-phase. Data weretomy (n Å 28).expressed as the mean { SD and the unpaired Wilcoxon’sGroup 5. Animals were subjected to common bile duct ob-test was used for comparison between groups. Difference wasconsidered significant at P õ .05.

RESULTS

Experiment 1

The T bili level was not increased during the experi-ment in any groups (Table 1). The ALT level increasedrapidly in the 12 hours after hepatectomy and thengradually decreased again in all three groups. How-ever, the mean ALT level was significantly higher ingroup 1 than in groups 2 or 3 at 12, 24, and 48 hours(Table 2). The LTB4 level reached a peak 12 hours afterFIG. 2. Graphic representation of the timing of operative proce-

dures and drug administration of experiment 2. hepatectomy and gradually decreased in group 1, but

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546 URADE, IZUMI, AND KITAGAWA HEPATOLOGY March 1996

TABLE 2. Changes of Serum ALT Levels Significant differences in LI were not observed betweengroup 4 and group 5 at 12 and 48 hours after hepatec-ALT (IU/L)tomy, and the LI was significantly higher in group 5

Group 0 h 12 h 24 h 48 h at 24 hours than that in group 4 (Table 4).1 71 { 17 921 { 131 675 { 69 290 { 272 ND 497 { 81* 339 { 26* 219 { 37* DISCUSSION3 ND 518 { 133* 385 { 119* 216 { 30*

LT is a generic term for unsaturated fatty acids with4 280 { 77 1,332 { 447 1,061 { 331 411 { 321three conjugated double bonds, and these substances5 289 { 61 666 { 140† 657 { 121† 387 { 196are derived from the arachidonic acid cascade by me-

NOTE. Values are mean { SD (n Å 28, per group). tabolism of 5-lipoxygenase. Various chemical, physio-Abbreviation: ND, not determined. logical, or biologic stimuli cause arachidonic acid to be* P õ .01 vs. group 1. liberated from the phospholipid bilayer of cell mem-† P õ .01 vs. group 4.

brane by phospholipase A2. Subsequently, a number ofphysiologically active substances are produced fromthis parent compound, with the 5-lipoxygenase system

no increase was observed in group 2 or 3, and a signifi- being responsible for producing LTB4, LTC4, LTD4,cant difference was found between group 1 and group and LTE4. LTC4, LTD4, and LTE4 were originally2 or 3 after hepatectomy (Table 3). The LI was signifi- known as the slow-reacting substances of anaphylaxis,cantly higher in group 2 or 3 than in group 1 at 24 and and they have been shown to contribute extensively to48 hours after hepatectomy (Table 4). the pathogenesis of bronchial asthma and anaphylactic

shock. LTB4 promotes the migration of leukocytes andExperiment 2 macrophages as well as activating these cells, and thus

accelerates various immunologic and inflammatory re-The T bili level was increased at 1 week after theligation of common bile duct in group 4 and group 5 actions. LTB4 is primarily produced in the Kupffer cells

and endothelial cells of liver sinusoids, as well as byand decreased rapidly to nearly normal levels within48 hours after the release of obstruction and concurrent blood cells such as neutrophils, monocytes, and macro-

phages. It was recently shown that LTB4 is also pro-hepatectomy. There was no significant difference in Tbili level between the animals who received AA-861 duced by hepatocytes.13 LTB4 is inactivated by cyto-

chrome p-450 enzymes and is excreted with the bileand those who did not (Table 1). ALT levels also in-creased after obstruction of the common bile duct, but into the intestinal tract.8 Because of disruption of bili-

ary outflow into the duodenum, LTB4 excretion wasa significant difference was not observed between thegroups before hepatectomy. The ALT level increased remarkably inhibited; therefore, a marked increase of

the blood LTB4 level occurred during obstructive jaun-rapidly in the 12 hours after hepatectomy and thengradually decreased again in both groups. However, dice in the present study.

There have been many studies of hepatic regenera-the mean ALT level was significantly higher in group4 than in group 5 at 12 and 24 hours after hepatectomy tion after jaundice or hepatectomy,14 but reports on

regeneration after hepatectomy with simultaneous re-(Table 2). The whole blood LTB4 level increased duringthe period of obstructive jaundice but a significant dif- lease of obstructive jaundice are scarce. We developed

a model of temporary jaundice in rats to examine theference was not observed between the groups beforehepatectomy. The LTB4 level reached a peak 24 hours influence of LTB4 and obstructive jaundice on liver re-

generation after partial hepatectomy. AA-861 is aafter hepatectomy in groups 4 and 5. The LTB4 levelin group 5 was significantly lower than that in group strong selective inhibitor of 5-lipoxygenase and does

not affect the level of cyclooxygenase activity.15 Ashida4 at 12, 24, and 48 hours after hepatectomy (Table 3).

TABLE 3. Changes of LTB4 in Whole Blood

LTB4 (pg/mL)

Group 0 h 12 h 24 h 48 h

1 231 { 112 1,987 { 1,574 1,707 { 1,134 577 { 2492 ND 191 { 29* 282 { 74* 303 { 43‡3 ND 198 { 46* 297 { 72‡ 303 { 49‡4 2,267 { 661 4,451 { 2,150 5,801 { 1,285 3,759 { 1,2535 2,197 { 575 1,881 { 967† 2,251 { 1,573‡ 1,754 { 497†

NOTE. Values are mean { SD (n Å 28, per group).* P õ .01 vs. group 1.† P õ .01 vs. group 4.‡ P õ .05 vs. group 1.Abbreviation: ND, not determined.

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HEPATOLOGY Vol. 23, No. 3, 1996 URADE, IZUMI, AND KITAGAWA 547

TABLE 4. Changes of BrdU LI dice. This suggests that the liver was already primedfor regeneration of hepatocyte injury caused by obstruc-BrdU LI (%)tive jaundice. Trams et al.14 have reported that an in-

Group 0 h 12 h 24 h 48 h crease of hepatocyte mitotic activity could be observedwithin 3 days of biliary obstructions in rats. However,1 0 0 21.6 { 8.2 10.7 { 1.6

2 0 0 45.5 { 5.3* 12.2 { 0.9c when the obstruction continues for too long, liver dys-3 0 0 45.6 { 2.8* 12.2 { 1.2c function becomes irreversible, and regeneration is in-4 4.7 { 3.1 1.6 { 2.3 20.8 { 1.6 20.7 { 7.0 hibited even if the obstruction is released.22 Aronson23

5 2.6 { 2.5 2.4 { 1.8 42.1 { 4.5d 21.0 { 9.7 found that the limit for recovery from hepatic injuryinduced by obstructive jaundice was 2 weeks. Thus,NOTE. Values are mean { SD (n Å 28 per group).liver dysfunction was reversible, and regeneration was* P õ .01 vs. group 1.not inhibited, because the duration of obstruction was† P õ .01 vs. group 4.

‡ P õ .05 vs. group 1. 1 week in the present study, and further investigationof the effect of longer periods of obstruction may benecessary.

The involvement of 5-lipoxygenase metabolites in he-et al.16 have shown that AA-861 suppresses LTB4 pro-duction in rat peritoneal macrophages.16 In the present patocyte injury has rarely been studied.24 LTB4 is not

considered to directly injure hepatocytes but is thoughtstudy, suppression of LTs production by the daily ad-ministration of AA-861 promoted liver regeneration. to be involved indirectly in hepatopathy. Various cyto-

kines such as interleukin-2 or interferon gamma areThe effect was similar at doses of 20 and 40 mg/kg ofAA-861, and it did not show any toxicity at these doses. produced in response to LTB4,25 and the inflammatory

cells activated by these cytokines then cause damageThus, AA-861 administration at 20 mg/kg/d was suffi-cient to suppress the increase of LTB4 caused by ob- to hepatocytes. Because AA-861 blocks 5-lipoxygenase

metabolic pathway, the production of LTC4, LTD4, andstructive jaundice and partial hepatectomy in this ratmodel. LTE4 is inhibited as well as that of LTB4. It is 5-lipoxy-

genase inhibition rather than LTB4 suppression thatAn increase of LTB4 level was observed after partialhepatectomy in both normal and icteric rat, and AA- is really effective for liver regeneration. LTB4 is simply

a parameter of the action of AA-861. LTC4 has been861 suppressed LTB4 production after partial resectionof icteric liver. The increases of LTB4 after hepatectomy implicated in causing hepatocyte injury. For example,

Mizoguchi et al.26 reported that LTC4 caused damagewere probably attributable to activation of the 5-lipoxy-genase pathway by local liver injury, which was shown to suspension of hepatocytes. Kioka et al.27 reported

that there are nearly 1,500 specific receptors per hepa-by an increase of the serum ALT level. Impaired clear-ance of endotoxin caused by partial hepatectomy can tocyte for LTC4, but no LTB4 receptors. Thus, among

LTs whose excretory pathway is impaired by bile flowbe considered as an alternative reason for the increasein the LTB4. Endogenous endotoxin is produced by the obstruction, LTB4 is thought to injure the liver indi-

rectly and LTC4 directly. Therefore, the inhibition ofintestinal bacterial flora and is transported via the por-tal circulation to hepatic Kupffer cells in which phago- 5-lipoxygenase suppressed the production of LTs and

allowed the promotion of liver regeneration.cytosis occurs.17 Because 70% hepatectomy also de-creases Kupffer cell population, excess endotoxin may It has been widely accepted in Japan that the preop-

erative relief of obstructive jaundice is required to per-not be effectively cleared.18-20 An increase of endotoxinlevels would promote metabolism of the 5-lipoxygenase form the hepatic resection safely.28 However, some

Western authors have suggested that a waiting periodsystem in the liver and throughout the body.8,21 Be-cause endogenous endotoxin production is enhanced in between the relief of jaundice and tumor resection may

lead to the expansion of cancer.29-31 Therefore, it is ad-obstructive jaundice,8 predisposition to endotoxemiamay occur after hepatectomy with prior obstruction of visable to perform surgery as early as possible when

hepatectomy can be performed safely in icteric pa-the bile flow. The LTB4 level also increases in obstruc-tive jaundice because the excretory pathway to the duo- tients. The results obtained in this study suggest that,

in the future, hepatectomy may perhaps be performeddenum is blocked. The peak LTB4 level occurred at12 hours after hepatectomy in normal rats, but was more safely in patients with obstructive jaundice when

the production of LTs is reduced by therapy with safeobserved at 24 hours after hepatectomy in icteric rats.This was probably caused by the inability of the icteric and harmless 5-lipoxygenase inhibitors.rats to rapidly excrete accumulated LTB4 even after

Acknowledgment: The authors thank our chief Pro-bile duct obstruction was relieved.fessor Itsuo Miyazaki for his useful advice. In addition,The LI measures DNA synthesis by thymidine ana-the authors thank our laboratory staff for their techni-logue incorporation into the nuclei of S-phase cells. Itcal assistance.also indirectly indicates the ability of the liver to regen-

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