ORIGINAL ARTICLE

Losartan Supports Liver Regrowth via Distinct Boost of PortalVein Pressure in Rodents with 90 % Portal Branch Ligation

Kezhou Li • Xiaohong Qi • Jiaying Yang •

Jianping Gong • Chunlu Tan • Qingjie Xia •

Jieran Long • Zhongdin Wang

Received: 27 February 2012 / Accepted: 27 March 2013 / Published online: 30 April 2013

� Springer Science+Business Media New York 2013

Abstract

Objectives The study used a model of 90 % portal branch

ligation (PBL) in rats to study the effect of losartan on

portal vein pressure (PVP) and liver regeneration in rats

after PBL.

Methods A total of 144 male Sprague–Dawley rats were

arbitrarily designated into three treatment method groups: a

sham operation group (Sham), a PBL treatment group

(PBL), and a PBL plus losartan treatment group

(PBL ? L). Losartan (2 mg/day) was intragastrically ga-

vaged 3 days before the PBL or sham operation to time

points of study.

Results Both the PBL and PBL ? L groups showed an

intense surge in PVP after PBL treatment, peaking at 12 h

postsurgery, then lessening progressively afterwards. PVP

was substantially greater in these two groups compared

with the Sham group at 6–72 h postsurgery (p \ 0.01).

Compared with the PBL group, the PBL ? L group

showed a noticeable reduction in PVP 6–48 h postsurgery

(p \ 0.05); the PBL group showed considerably raised

levels of plasma ALT and AST 6–72 h postsurgery

(p \ 0.01). Compared to the PBL group, the PBL ? L

group showed drastically reduced plasma ALT and AST

levels 12–72 h postsurgery (p \ 0.05).

Conclusions Losartan supports liver regeneration in 90 %

of rats that underwent PBL. The mechanism may be related

to losartan’s ability to regulate PVP and increase serum

hepatocyte growth factor levels.

Keywords Liver regeneration � Portal branch ligation �Hepatocyte growth factor � Losartan

Introduction

Extended hepatectomy is the recommended treatment for

large liver malignancies, hilar cholangiocarcinoma (CCA),

and colorectal liver metastasis [1]. Conversely, inadequate

functional remnant liver (FRL) volume can cause postop-

erative fatality by inducting hepatic complications, a

component that often restricts the scientific application of

this treatment [2, 3]. To decrease postoperative risk, some

investigators recommend using portal vein embolization

(PVE) as a preoperative measure to enhance the prognosis

for extended hepatectomies, with reassuring outcomes.

Functional remnant liver volume can be enhanced by

means of compensatory hypertrophy induced by preoper-

ative selective hepatic PVE. Subsequently, PVE may not

only improve the surgical safety of radical liver resection,

but also improve successful outcomes in some patients [4].

Even with PVE, however, radical liver resection may not

be suitable for 5–36 % of patients due to insufficient

contralateral hepatic hypertrophy [5]. Liver regeneration is

Kezhou Li and Xiaohong Qi contributed equally to this work.

K. Li � X. Qi � J. Yang (&) � C. Tan � Z. Wang

Department of Hepatobiliopancreatic Surgery, West China

Hospital, Sichuan University, Chengdu 610041, Sichuan

Province, China

e-mail: hepatobiliary@163.com

J. Gong

Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing

Medical University, Chongqing, China

Q. Xia

Advanced Medical Center, West China Hospital, Sichuan

University, Chengdu, China

J. Long

Department of Oncology, West China Hospital, Sichuan

University, Chengdu, China

123

Dig Dis Sci (2013) 58:2205–2211

DOI 10.1007/s10620-013-2664-3

a sophisticated and stringently performed course of action,

influenced by the complicated network of signaling path-

ways that integrate extracellular signals, along with a

cascade of intracellular molecular events. Numerous

growth components and cytokines are involved during liver

regeneration in animal models; similar components may

also occur in human liver regeneration [6, 7]. Of the

acknowledged components, hepatocyte growth factor

(HGF) is the most essential proliferation revitalizing

component, along with mitogen, which could mature liver

cells. Liver regeneration can be promoted through esca-

lating serum HGF levels in several animal models for liver

regeneration [8–10].

Scientific studies propose that angiotensin II is actually a

highly effective inhibitor of HGF. Implementing angio-

tensin II receptor 1 (AT1) antagonist also has been proven

to minimize lesions of the cardiovascular and pulmonary

systems by increasing serum HGF levels in animal models

of diabetes and pulmonary fibrosis [11, 12]. However, the

results of AT1 antagonist on serum HGF levels and liver

regeneration in 90 % of PBL rats have not been docu-

mented. Research has shown that, as a possible AT1

antagonist, losartan can minimize portal vein pressure

(PVP) in patients with portal hypertension in liver cirrho-

sis. The consequence of losartan on PVP, however, as a

result of stages after PVE has not yet been shown. For this

reason, our research addresses the consequences of losartan

on PVP, serum HGF levels, and liver regeneration in rats

after 90 % PBL.

Materials and Methods

Animal Experiments

A total of 144 male Sprague–Dawley rats (8 weeks old),

weighing 180–220 g, obtained from the Laboratory Animal

Center, West China Center of Medical Science, were used in

our study. The rats consumed conventional water and food

under controlled temperature and moisture and a 12-h light/

dark cycle. All rats in the study were observed for 1 week,

then randomized into three groups: the sham operation group

(Sham group); the model group (PBL only), and the treat-

ment group (PBL ? losartan 2 mg/kg 9 day). The rats were

anesthetized by injection of 1.5 % sodium pentobarbital

(40 mg/kg) into the abdominal cavity. Under the micro-

scopic lense, portal vein branches, which provide to the

median, left, and right lateral lobes of the liver, were sepa-

rated and ligated carefully. Only portal vein branch supply to

the caudate lobe was preserved. During this process, proper

care was taken to not damage the hepatic artery and bile

ducts. The ligated liver lobes comprised 90 % of the liver

weight. All PBL surgeries were performed between 9:00 and

12:00 a.m. In the sham operation group, the portal vein

branches were dissociated but not ligated, and the abdominal

cavity was then closed immediately. Daily for 3 days before

surgery until the end of the experiment, the sham operation

group and the PBL group received physiological saline,

whereas the PBL ? L group was given losartan.

Portal Vein Pressure, Blood Samples, and Liver

Samples

To measure PVP, the abdomen was opened along the ori-

ginal incision under anesthetization at 6, 12, 24, 48, 72,

120, or 168 h after surgery for each of the groups. An

electronic manometer (Nihon Kohden, Tokyo, Japan) with

a heparinized 22-gauge needle was inserted directly into

the portal vein to measure PVP. The zero graduation line

was defined by the anatomical position of portal vein, and

results were indicated in millimeters of mercury. All blood

samples were taken directly from the heart immediately

after liver extraction and centrifuged. The levels of ALT

and AST in the sera were detected with a standard clinical

automatic analyzer (Arkray, Kyoto, Japan). The complete

livers were surgically removed, blood was blotted with

filter paper, and the tissue was observed for color and

texture. The unligated liver lobes were maintained in 20 %

buffered formalin. The mass of unligated liver lobes and

total liver were weighed (accurate to 0.01 g), and LW/TW

index was calculated.

Histology and Immunohistochemistry

The unligated liver lobes taken from each time point were

fixed with 10 % formaldehyde, embedded in paraffin, and

sliced into 4-lm sections. Hepatic tissue sections were

routinely dewaxed and stained with hematoxylin and

eosin (H&E) to observe the pathological changes in liver

structures. Proliferating cell nuclear antigen (PCNA) in

unligated liver lobes was assayed immunohistochemically

using the S–P method, then incubated at 1:100 dilution

for 60 min with polyclonal antibody against mouse PCNA

(Santa Cruz Biotechnology, Santa Cruz, CA, USA). After

washing with Tris-buffered saline, sections were incu-

bated with the secondary antibody and immunostained by

the EnVision (Dako A/S, Grostup, Denmark) method

according to instructions. The criterion for immunohisto-

chemical-positive cells in terms of PCNA index was

brown-yellow stained nucleus with a distinct boundary.

Each section was counted for PCNA-positive nuclei in at

least five random areas, at 2009 magnification ([300

cells), and the percentages of labeled nuclei were

calculated.

2206 Dig Dis Sci (2013) 58:2205–2211

123

Assays of HGF in Plasma

The plasma concentration of HGF was detected using the

ELISA method (HGF Assay Kit, Institute of Immunology,

Tokyo, Japan). The value of A492 was determined by

WellscanMK-3 type. Based on different concentrations of

standard serum A value, the specification curve and HGF

concentrations were attained.

Statistical Analysis

Data were expressed as mean ± SEM and analyzed by

t test or Pearson correlative analysis with SPSS II.5 soft-

ware. p values B0.05 were considered statistically

significant.

Results

Losartan Inhibits Rise of PVP

The normal value of PVP in rats is approximately

10.56 ± 0.75 mmHg. Compared with that in the sham

operation group, the PVP of rats in the PBL group and the

PBL ? L group increased sharply after PBL. For these two

groups, postsurgery PVP peaked at 12 h and then gradually

decreased to normal levels approximately 120 h after sur-

gery. The average PVP of the PBL group was significantly

higher than that of the sham operation group between 6 and

72 h (p \ 0.01), whereas the PVP of the PBL ? L group

decreased significantly at 6–48 h after surgery (p \ 0.05)

(Fig. 1).

Losartan Inhibits the Increase of ALT and AST Levels

The typical ALT level in rats is approximately

40.33 ± 7.09. The ALT levels in the PBL group increased

rapidly after PBL, peaking (488.83 ± 41.80) at 24 h after

surgery, then decreased gradually. Compared with ALT

levels in the sham operation group, ALT levels in the PBL

group increased dramatically between 6 and 72 h

(p \ 0.01). The ALT levels in the PBL ? L group were

significantly higher than those in the sham operation group,

yet significantly lower than those in the PBL group

between 12 and 72 h postsurgery (p \ 0.01 or p \ 0.05)

(Fig. 2).

The AST levels in rats are typically approximately

75.00 ± 17.09. After PBL, AST levels in the PBL group

peaked (806.16 ± 59.56) at 12 h, and then dropped grad-

ually. The AST levels in the PBL group were significantly

higher than those in the sham operation group at 6–72 h

postsurgery (p \ 0.01). In comparison with the PBL group,

AST levels in the PBL ? L group decreased gradually

after 12 h and reached a normal level at 72 h. Between 6

and 72 h, AST levels in the PBL ? L group were signifi-

cantly lower than those in the PBL group (p \ 0.01 or

p \ 0.05) (Fig. 3).

Fig. 1 PVP values at the various time points after surgical treatment

(millimeters of mercury ±s). PVP values are clearly higher in both

the PBL and PBL ? losartan groups compared with the sham-

operation group; however, PVP in PBL ? losartan group is lower

than that in the PBL group. *p \ 0.01 versus sham-operation group;

**p \ 0.01 or p \ 0.05 versus the PBL group

Fig. 2 Serum ALT value after 90 % PBL at different time points

(U/L, ±s). ALT values were clearly higher in both the PBL and the

PBL ? losartan groups compared with the sham-operation group;

however, ALT in the PBL ? losartan group was lower than that in the

PBL group. *p \ 0.01 versus sham operation group; **p \ 0.01 or

p \ 0.05 versus PBL group

Dig Dis Sci (2013) 58:2205–2211 2207

123

Losartan Increases the Plasma Concentration of HGF

Portal branch ligation resulted in a rise in plasma HGF

concentrations in both the PBL group and the PBL ? L

group. After PBL, HGF levels in the PBL group reached

seven times their initial preoperative values. HGF

concentrations then decreased gradually, finally maintain-

ing a level of approximately 2.0 ng/ml after 168 h. Com-

pared with HGF levels in the PBL group, HGF levels in the

PBL ? L group were notably higher between 6 and 168 h

postsurgery and remained significantly higher at 168 h

postsurgery (p \ 0.01) (Fig. 4).

Losartan Increases the PCNA Index

The PCNA index was used to evaluate cell proliferation

in vivo in the regenerating liver after PBL. The basic value

of the PCNA index is 5.55 % in rat liver tissue. In the PBL

group, the PCNA index was significantly elevated by 12 h

after PBL, and peaked at 120 h. Compared with that in the

sham operation group, the PCNA index was significantly

higher between 12 and 168 h (p \ 0.01). For the PBL ? L

group, the PCNA index peaked at 72 h. Compared with

that in the PBL group, the PCNA index for the PBL ? L

group was significantly elevated at 12–168 h postsurgery

(p \ 0.01 or p \ 0.05) (Figs. 5, 6a–c).

Losartan’s Effects on the LW/TW Ratio

After PBL, the ligated liver lobes atrophied and darkened,

whereas the unligated liver lobes underwent hypertrophy.

In the sham operation group, the caudate lobe accounted

for 10 % of the liver weight. Compared with the LW/TW

ratio in the sham operation group, the LW/TW ratio in the

PBL group increased significantly from 24 h (p \ 0.01),

increasing gradually, reaching 27.83 % by 168 h

Fig. 3 Serum AST value after 90 % PBL at different time points (U/

l, ±s). AST values were obviously higher in both the PBL and

PBL ? losartan groups compared with the sham operation group;

however, AST in the PBL ? losartan group is lower than that in the

PBL group. *p \ 0.01 versus sham operation group; **p \ 0.01

versus PBL group

Fig. 4 HGF levels after PBL at different time points (ng/ml, ±s).

HGF values are higher in both the PBL and PBL ? losartan groups

compared with the sham operation group; however, HGF in the

PBL ? losartan group is higher than that in the PBL group. *p \ 0.01

versus sham operation group; **p \ 0.01 or p \ 0.05 versus PBL

group

Fig. 5 PCNA indexes after PBL at different time points. *p \ 0.01

versus sham operation group. PCNA values clearly higher in both the

PBL and the PBL ? losartan groups compared with the sham

operation group; however, PCNA in the PBL ? losartan group is

higher than that in the PBL group. **p \ 0.01 versus PBL group

2208 Dig Dis Sci (2013) 58:2205–2211

123

postsurgery. The LW/TW ratio for the PBL ? L group

reached 31.15 % by 168 h postsurgery. In the PBL ? L

group, the LW/TW ratio was higher than that in the PBL

group between 24 and 168 h postsurgery (p \ 0.01)

(Fig. 7).

Pathologic Changes in Hepatic Tissue

In the sham operation group, the hepatic cells arrayed

radially around the central vein. After PBL, cells of unli-

gated liver lobes showed slight edema and hepatic sinu-

soids dilated significantly by 24 h. Hepatic lobules were

severely distorted by 72 h. Thereafter, the hepatic tissue

gradually returned to normal. In the PBL ? L group,

hepatocyte edema and dilation of hepatic sinusoids were

less severe than in the PBL group, and took less time to

return to normal. In both the PBL group and the PBL ? L

group, the number of mitotic-phase hepatocytes were

significantly higher than in the sham operation group

(Fig. 8a–c).

Discussion

Significant hepatectomy is the recommended treatment for

patients with enormous liver tumor, CCA, or hepatocellular

carcinoma (HCC). Although this course of action is carried

out to extend life expectations, it also offers the probability

of resulting in hepatic malfunction due to the substantial

removals of hepatic tissue. Consequently, numerous

affected patients are regarded as not suitable candidates for

this surgical treatment because of inadequate liver remnant

volume [13]. There is considerable agreement at numerous

hepatic surgical centers that when future liver remnant

(FLR) is B20 % of the standardized total liver volume,

both the postoperative mortality rate and the incidence of

complications after hepatic resection increase appreciably.

For patients with cirrhosis or having received large-dose

chemotherapy, this percentage should be to B40 and

B30 %, respectively [14]. Preoperative PVE is actually a

contrasting technological innovation currently in use to

enhance the degree and performance for the FLR in an

effort to reduce the probability of complications from

major hepatectomy for HCC or CCA. Embolization of the

portal vein branches feeding the liver segment which

would be resected makes it possible for redistribution of

the portal circulation of blood toward the branches for the

FRL. Consequently, the effective use of PVE before

expanded hepatectomy not only adds to the applicability of

the course of action, but additionally allows for surgical-

safe practices [15, 16]. Recently, the use of PVE to manage

inadequate FLR in patients requiring major hepatectomy

has become more common.

The adjustment of portal vein blood circulation hemo-

dynamics is an additional prospective reason for hepatic

failure after extensive hepatectomy. With substantial

hepatic resection, the portal vein blood flow offering the

remnant hepatic tissue increases dramatically. Subse-

quently, PVP results in being enhanced, which enables it to

Fig. 6 a PCNA expression in normal rat liver tissue (9200). b PCNA expression at 72 h after PBL in the PBL group (9200). c PCNA

expression at 72 h after PBL in the PBL ? L group (9200)

Fig. 7 LW/TW ratios after PBL at different time points. LW/TW

ratios are clearly higher in both the PBL and the PBL ? losartan

groups compared with the sham operation group; however, LW/TW

ratios in the PBL ? losartan group are higher than those in the PBL

group. **P \ .01 versus PBL group

Dig Dis Sci (2013) 58:2205–2211 2209

123

skimp on the dwelling with the remaining hepatic sinusoids

and thus triggering hepatic injury and inhibition of liver

regeneration [17–21]. This stress represents sinusoidal

endothelial cell injury, which results in future hepatocel-

lular damage and death [22, 23]. In the same manner,

injury to nonembolized segments accompanies the steep

surge in PVP in patients undergoing PVE. In our research,

transient portal hypertension and excessive hepatic blood

flow were observed after PBL. Our research also showed

that substantial amounts of serum ALT and AST comple-

mented the portal hypertension after PBL, which suggests

liver dysfunction. In the mean time, the phenomenon of

liver organ injuries (e.g., hepatic sinusoids dilation and

hepatocellular edema) was seen during the early phases

after PBL. We found, however, that PVP, ALT, and AST

were clearly lower in the PBL ? losartan group than in the

PBL group.

Conversely, resulting from insufficient FLR regrowth,

not every patient who undergoes PVE is able to undergo

significant hepatectomy [23, 24]. To overcome this obsta-

cle, we try to enhance liver regeneration after PBL with the

administration of specified drugs such as losartan. In the

course of liver regrowth after PBL, ordinarily quiescent

hepatocytes require models of reproduction to revive the

liver mass by means of hyperplasia. Liver regeneration is

actually a complicated and highly regulated course of

action, manipulating a complicated network of signaling

pathways that integrates extracellular signals in addition to

a cascade of intracellular molecular events.

Many advanced components and cytokines are essential

to the process of liver regrowth in animal models. In

addition, the expression of such components also occurs

during human liver organ regrowth. Furthermore, TNF-a,

TGF-a, and IL-6, HGF is regarded as essentially the most

significantly proliferative revitalizing component, along

with mitogen, to the mature liver cells, for its role in pro-

moting liver regeneration and as protection of liver tissue

via decreasing apoptosis of hepatic cells. HGF can be

considered a morphogenic, motogenic, or mitogenic

substance, depending on its variety of activities. Study

results propose that escalating serum HGF levels promote

liver regeneration. Numerous studies have also shown that

angiotensin is actually an efficient inhibitor of HGF, rec-

ognizing that use of AT1 antagonists can maximize serum

HGF levels [25–27]. Losartan clearly is this type of AT1

antagonist; it blocks various endogenous and exogenous

pharmacological results of angiotensin.

Our research established that plasma HGF levels began

to increase at 6–168 h after PBL, peaking at 6 h, and

progressively lessening. Compared with the PBL group,

serum HGF quantities in the PBL ? L group enhanced

significantly and maintained an advanced level even at

168 h postsurgery. The PCNA labeling index is undoubt-

edly a gauge capable of appraising liver organ regrowth.

With simplex PBL, PCNA labeling indexes progressively

enhanced and peaked at 120 h, and the quantity of positive

cells visibly increased within the liver tissue. With the use

of losartan, PCNA indexes for the PBL ? L group were

substantially higher than those within the PBL group,

starting 12 h after PBL. Consequently, we consider that the

effective use of losartan may possibly encourage hepato-

cyte proliferation within our 90 % PBL rat model. The

ratio of LW/TW is yet another essential indicator to

appraise liver regeneration. In our study, we observed that

the LW/TW ratio for the PBL ? L group was significantly

higher than that in the PBL group, starting at 24 h after

PBL. With this finding, we could consider that losartan

supports substantial recuperation of liver organ volume

level. The existing research also supports our speculation

that mechanisms through which losartan promotes liver

regeneration are most likely associated with its ability to

assist in the details about serum HGF.

Conclusions

Administration of losartan can hinder the increase in PVP

as a result of phases following PBL, liver organ damage,

Fig. 8 a Normal rat liver tissue HE 9200. b Pathological changes at 24 h after PBL in the PBL group HE 9200. c Pathological changes at 24 h

after PBL in the PBL ? L group HE 9200

2210 Dig Dis Sci (2013) 58:2205–2211

123

and thus indirectly encourage liver organ regrowth. Human

studies might be necessary to investigate the efficacy and

safety of this technique in the medical setting.

Conflict of interest None.

References

1. Aussilhou B, Hubert C, Francoz C, et al. Extended liver resection

for polycystic liver disease can challenge liver transplantation.

Ann Surg. 2010;252:735–743.

2. Yasuji S, Masatoshi M. Current surgical treatment for bile duct

cancer. World J Gastroenterol. 2007;13:1505–1515.

3. Ueda A, Yoshidome H, Kaqawa S, et al. Two-stage hepatectomy

procedure combined with portal vein embolization to achieve

curative resection for initially unresectable multiple and bilobar

colorectal liver metastases. Ann Surg. 2004;240:1037–1049.

4. Abulkhir A, Limoqelli P, Healey AJ, et al. Preoperative portal

vein embolization for major liver resection: a meta-analysis. Ann

Surg. 2008;247:49–57.

5. Liska V, Treska V, Mirka H, et al. Interleukin-6 augments acti-

vation of liver regeneration in porcine model of partial portal vein

ligation. Anticancer Res. 2009;29:2371–2378.

6. Ribeiro MA Jr. Liver regeneration, stem cells and beyond. World

J Gastrointest Surg. 2009;1:6–7.

7. Campbell JS, Prichard L, Schaper F, et al. Expression of sup-

pressors of cytokine signaling during liver regeneration. J Clin

Invest. 2001;107:1285–1292.

8. Nelson F, Jean SC, Kimberly JR, et al. Liver regeneration.

Hepatology. 2006;46:S45–S53.

9. Huh CG, Factor VM, Sanchez A, et al. Hepatocyte growth factor/

c-met signaling pathway is required for efficient liver regenera-

tion and repair. Proc Natl Acad Sci USA. 2004;101:4477–4482.

10. Nakao T, Arii S, Kaido T, et al. Heparin accelerates liver

regeneration following portal branch ligation in normal and cir-

rhotic rats with increased plasma hepatocyte growth factor levels.

J Hepatol. 2008;37:87–92.

11. Feng H. Effects of losartan on the treatment of experimental

pulmonary fibrosis and its mechanism. Wuhan Univ (Med Sci).

2009;30:484–487.

12. Xiaohua W, Shi Liang Y, Ping Y, et al. Effects of telmisartan

liver cell growth factor in diabetic rat. Cell Mol Immunol.

2009;25:1177–1182.

13. Ribero D, Abdalla EK, Thomas MB, et al. Liver resection in the

treatment of hepatocellular carcinoma. Expert Rev Anticancer

Ther. 2006;6:567–579.

14. Yokoyama Y, Nagino M, Nimura Y. Mechanisms of hepatic

regeneration following portal vein embolization and partial hep-

atectomy: a review. World J Surg. 2007;31:367–374.

15. Starzl TE, Francavilla A, Halgrimson CG, et al. The origin,

hormonal nature, and action of hepatotrophic substances in portal

venous blood. Surg Gynecol Obstet. 1973;137:179–199.

16. Di Stefano DR, de Baere T, Denys A, et al. Preoperative percu-

taneous portal vein embolization: evaluation of adverse events in

188 patients. Radiology. 2005;234:625–630.

17. Jiang S-M, Zhou G-W, Zhang R, et al. Role of splanchnic

hemodynamics in liver regeneration after living donor regenera-

tion. Liver Transpl. 2009;15:1043–1049.

18. Troisi R, de Hemptinne B. Clinical relevance of adapting portal

vein flow in living donor liver transplantation in adult patients.

Liver Transpl. 2003;9:S36–S41.

19. Troisi R, Ricciardi S, Smeets P, et al. Effects of hemi-portocaval

shunts for inflow modulation on the outcome of small-for-size

grafts in living donor liver transplantation. Am J Transplant.

2005;5:1397–1404.

20. Kobayashi T, Sato Y, Yamamoto S, et al. Augmentation of heme

oxygenase-1 expression in the graft immediately after implanta-

tion in adult living-donor liver transplantation. Transplantation.

2005;79:977–980.

21. Demetris AJ, Kelly DM, Eghtesad B, et al. Pathophysiologic

observations and histopathologic recognition of the portal hyp-

erperfusion or small-for-size syndrome. Am J Surg Pathol.

2006;30:986–993.

22. Man K, Lee TK, Liang TB, et al. FK 409 ameliorates small-for-

size liver graft injury by attenuation of portal hypertension and

down-regulation of Egr-1 pathway. Ann Surg. 2004;240:159–168.

23. Xu X, Man K, Zheng SS, et al. Attenuation of acute phase shear

stress by somatostatin improves small-for-size liver graft sur-

vival. Liver Transpl. 2006;12:621–627.

24. Abdalla EK. Resection of colorectal liver metastases. J Gastro-

intest Surg. 2011;15:416–419.

25. Nakano N, Morishita R, Moriguchi A, et al. Negative regulation

of local hepatocyte growth factor expression by angiotensin II

and transforming growth factor-beta in blood vessels: potential

role of HGF in cardiovascular disease. Hypertension. 1998;32:

444–451.

26. Yo Y, Morishita R, Yamamoto K, et al. Actions of hepatocyte

growth factor as a local modulator in the kidney: potential role in

pathogenesis of renal disease. Kidney Int. 1998;53:50–58.

27. Taniyama Y, Morishita R, Nakagami H, et al. Potential contri-

bution of a novel antifibrotic factor, hepatocyte growth factor, to

prevention of myocardial fibrosis by angiotensin II blockade in

cardiomyopathic hamsters. Circulation. 2000;102:246–252.

Dig Dis Sci (2013) 58:2205–2211 2211

123