|
|
The Role of Kupffer Cells After Major Liver Surgery
Hubert A. Prins*,
Catharina Meijer*,
Petra G. Boelens*,
Robert J. Nijveldt*,
Michiel P. C. Siroen*,
Sylvie Masson ,
Maryvonne Daveau,
Michel Scotté, ,
Jeroen Diks* and
Paul A. M. van Leeuwen*
From the * Department of Surgery, VU Medical
Center, Amsterdam, The Netherlands; Inserm U
519, Faculté de Médecine et de Pharmacie, Rouen, France; and the
Department of General and Digestive Surgery,
Charles Nicolle Hospital, Rouen, France
Correspondence: P. A. M. van Leeuwen, MD, PhD, Department of Surgery, VU
University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Electronic mail may be sent to
PAM.vLeeuwen{at}vumc.nl.
Background: Kupffer cells (KCs) are the resident macrophages of
the liver. KCs have an enormous endotoxin eliminating capacity. Endotoxins
play an important role in the development of systemic complications after
partial hepatectomy by activating KCs. The role of KCs and endotoxins after
partial hepatectomy is investigated. Methods: Wistar rats (n
= 16, 250–275 g) were randomly assigned to have 1 mL
dichloromethylene-diphosphonate (CL2MDP) or 1 mL NaCl 0.9% IV.
Forty-eight hours later, all rats received a two-thirds liver resection.
Twenty-four hours later, rats received at random 50 µg/kg endotoxin (LPS)
in 1 mL or 1 mL of NaCl 0.9% IV. The rats were killed 4 hours after LPS or SAL
infusion. Results: CL2MDP infusion resulted in a complete
KC elimination. KC-depleted rats had the lowest mean arterial pressure, the
highest heart and ventilatory rate after endotoxemia. All rats were able to
maintain pH in normal ranges. The KC-depleted rats after partial hepatectomy
had the lowest CO2 levels and the highest levels of lactate during
endotoxemia. Oxygen levels were similar in all groups. Hepatic, pulmonary, and
renal mRNA expression of tumor necrosis factor- (TNF-) and
interleukin-1β were decreased in KC-depleted rats. Plasma levels of
TNF- were significantly decreased in KC-depleted rats. Furthermore, the
highest influx of macrophages and polymorphonuclear cells in the lung and
kidney were measured in KC-depleted rats during endotoxemia.
Conclusions: Partial hepatectomy in KC-depleted rats result in a more
pronounced endotoxin-mediated systemic inflammation and decreased synthesis of
cytokines.
Kupffer cells (KCs) are the resident macrophages of the liver. KCs have an
enormous endotoxin eliminating capacity. Endotoxins play an important role in
the development of systemic complications after partial hepatectomy (PH) by
activating
KCs.2,3
Once activated, KCs start to release proinflammatory cytokines as tumor
necrosis factor- (TNF-), interleukin-1 (IL-1β),
interleukin-6 (IL-6) and interleukin-8
(IL-8).4–7
These cytokines mediate the systemic inflammatory response by inducing the
activation of other cell types such as endothelial cells, platelets,
monocytes, macrophages and polymorphonuclear cells
(PMNs).8
After PH, the remnant liver is exposed to these proinflammatory cytokines,
which are able to induce hepatocellular damage but are also necessary for
liver
regeneration.9–11
We have previously shown that KCs have a protective effect on the remnant
liver after
PH.12
There is little information about the role of KCs after PH with respect to
hemodynamics and systemic inflammation. To evaluate the role of KCs after PH,
dichloromethylene-diphosphonate (CL2MDP) was administered to
physically eliminate KCs.
We hypothesized that elimination of KCs after PH result in a deterioration
in hemodynamic and metabolic performance and an increase in the systemic
inflammatory response.
 |
MATERIALS AND METHODS
|
|---|
Animals
The study was approved by the Institutional Ethical Welfare Committee. Male
specific-pathogen-free Wistar rats, weighing 250–275 g, were obtained
from Harlan CPB, Zeist, The Netherlands. The animals were maintained in
accordance with the recommendations of the "Guide for the Care and Use
of Laboratory Animals" used in our institute (DHEW Publication No. [NIH]
85 to 23, revised 1985, Office of Science and Health Reports, DRR/NIH,
Bethesda, MD). The animals were allowed to acclimatize for at least 1 week
after arrival. They had free access to water and rat chow and were housed
under controlled environmental conditions (constant temperature, humidity, and
dark-light cycle). Surgeries and IV injections were performed under ether
anesthesia, unless stated otherwise.
Experimental Protocol
A two-thirds PH was performed according to the method of Higgins and
Anderson,13
consisting of resection of the median and left hepatic lobes after placing a
Vicryl ligature around the pedicles of these lobes. Forty-eight hours before
surgery, rats had been randomized to receive either 1 mL saline (NaCl 0.9%;
CON; n = 8) or 1 mL liposomes encapsulating the drug
CL2MDP IV (a gift of Boehringer Mannheim GmbH, Germany; n
= 8). The latter treatment was used as a method known as the so-called
macrophage suicide technique to achieve KC-depletion, as was described
previously.14,15
Thus, after surgery, rats were divided in 2 groups: CON (n = 8) and
CL2MDP (n = 8).
One day after PH, all rats were anesthetized by using ketamine
hydrochloride (50 mg/kg) intraperitoneally. The animals were placed in the
supine position on a heating pad to maintain rectal temperature at 37°C
± 0.5°C. The trachea was cannulated to facilitate breathing. The
right common carotid artery was cannulated using PE-50 tubing (Fisher
Scientific, Springfield, NY). The catheters were connected to P23Db Statham
pressure transducers. Pressure-wave monitoring was used to position the
carotid catheter into the carotid artery. After cannulation, rats were allowed
to stabilize for 30 minutes before the start of the experiment.
Twenty-four hours after PH, rats of each group were randomized again to
receive either 1 mL saline (NaCl 0.9%; SAL) or 50 µg/kg LPS (LPS) in 1 mL
IV. LPS was obtained from BACTO, DIFCO Laboratories, Detroit, MI; (BE coli
0127:B8, LD50 = 28.55 mg/kg). Thus, finally, 4 experimental groups
were studied (ie, CON-SAL, CON-LPS, CL2MDP-SAL, and
CL2MDP-LPS); in each group, n = 4.
During the experiment, mean arterial pressure (MAP) and heart rate (HR)
were recorded every 30 minutes. At the same time points, the ventilatory rate
(VR) was measured by counting the inspirational thoracoabdominal wall
movements. The animals were killed 4 hours after either SAL or LPS infusion by
rapid exsanguination.
Blood samples were drawn from the carotid catheter and collected in
heparinized pyrogen-free syringes. Blood gas analysis was performed
immediately upon blood withdrawal. All other blood samples were kept on ice
until centrifugation.
Plasma was obtained by centrifugation for 15 minutes at 1500 x
g at 4°C. All plasma samples were harvested in a laminar flow
cabinet to prevent contamination, and stored at –70°C until tested.
Upon PH, hepatic tissue samples of the resected liver lobes were obtained to
confirm KC-depletion by immunohistochemistry. Upon killing, tissue samples of
the liver, left lung, and left kidney were harvested. All tissue samples were
immediately frozen in liquid nitrogen and stored at –70°C until used
for immunohistochemical analysis or reverse-transcriptase polymerase chain
reaction (RT-PCR).
Immunohistochemical Assessment of KCs
To confirm the effect of CL2MDP-liposomes on the KC population,
cryostat sections of the resected liver lobes, obtained just after PH, were
stained with the monoclonal antibody (MAb) ED2 (Serotec, Hilversum, The
Netherlands) according to the method as previously
described.16,17
ED2 recognizes cell surface antigens of resident
macrophages.16
Endogenous peroxidase activity was blocked by using 0.3% (vol/vol)
H2O2 and 0.1% (wt/vol) sodium azide for 15 minutes to
prevent nonspecific staining of hepatic cells containing endogenous
peroxidase. At the end of the procedure, sections were stained for peroxidase
activity for 10 minutes with 0.5 mg/mL
3,3'-diaminobenzidinetetra-hydrochloride (Sigma, St Louis, MO) in 0.05 M
Tris-HCl buffer, pH 7.6, containing 0.03% (vol/vol)
H2O2. Finally, after rinsing in NaCl, sections were
slightly counterstained with hematoxylin, dehydrated and mounted in Entellan
(Merck, Darmstadt, Germany). Control sections were incubated in PBS instead of
MAb in the first step and examined for nonspecific staining. Treatment with
CL2MDP-liposomes resulted in <1% positive ED2 cells per
microscopic field (magnification x200) in both periportal and
pericentral areas of resected liver lobes. Thus, a nearly complete elimination
of KCs was achieved.
Blood Gas, Biochemical, and Hematologic Analysis
Blood gas analysis, including arterial pH, carbon dioxide tension
(PaCO2), oxygen tension (PaO2), and bicarbonate
(HCO3–) level was performed by using a commercial
blood gas analyzer (ABL 330; Radiometer, Copenhagen, Denmark). Plasma levels
of lactate were assessed by automated laboratory analysis.
Immunohistochemical Assessment of Pulmonary and Renal Macrophages and PMNs
The number of macrophages and PMNs was analyzed in cryostat sections of the
middle part of the left lung and kidney, obtained upon killing. The same
procedure as described for the immunohistochemical assessment of KCs by
staining with the MAb ED2 was used with certain modifications. Endogenous
peroxidase was not blocked, because PMNs were shown by taking advantage of
endogenous peroxidase activity. Instead of using ED2, sections were incubated
with the MAb ED1 (Serotec). ED1 recognizes a cytoplasmic antigen in monocytes
and the various types of macrophage
populations.18 The
immunohistochemical results concerning the number of hepatic KCs were analyzed
by calculating a mean percentage of ED2 positive cells per microscopic field
(10 x 20) in 3 periportal and 3 pericentral areas. The number of
ED1-positive cells (ie, KCs) and of cells with endogenous peroxidase activity
(ie, PMNs) per microscopic field (10 x 20) in pulmonary and renal tissue
obtained upon killing was observed in 3 separate sections of each sample. All
sections were analyzed by 1 observer in a blinded fashion.
Cellular RNA Extraction
Total RNAs were extracted from a frozen tissue sample according to a 1-step
method.19,20
Total cellular RNAs were obtained by sodium acetate-phenol-chloroform
extraction, and RNA concentration was measured by spectrophotometry at 260 nm.
The RNA preparations were controlled by agarose minigel electrophoresis with
visualization of the 18S and 28S ribosomal RNA bands after ethidium bromide
staining.
Assessment of Cytokine Gene Expression by Quantitative RT-PCR
RT-PCR was carried out as previously
described.20
Primers were chosen to have 50% to 60% GC content. Primer sequences were
chosen from separate exons of the rat genes so that RNA-associated PCR
products could readily be distinguished from any PCR product induced by
contaminating genomic DNA (data not shown). A RT-PCR for the housekeeping
β2-microglobulin gene provided an endogenous standard to
measure the loading homogeneity of different mRNAs. Preliminary experiments
(data not shown) revealed that 32 cycles for TNA- and IL-1β and 21
cycles for β2-microglobulin amplification were needed to give
a linear relationship between the number of cycles and the amount of PCR
product. Aliquots of PCR products were subjected to electrophoresis in a 6%
polyacrylamide gel and visualized under UV light after ethidium bromide
staining. The gels were dried and exposed onto x-ray films. Autoradiograms
were analyzed by computerized densitometric scanning using a Biocom equipment
mostly comprised of a CCD camera (Canon) and the Lecphor software. For
amplicon comparison, the values obtained by densitometric scanning were
expressed in arbitrary units and normalized as a function of the coamplified
β-microglobulin.
Assessment of TNF- Plasma Levels
Biologic TNF- activity was measured as described by Espevik and
Nissen-Meyer,21
using the murine fibrosarcoma WEHI 164 clone 13 cell line. Cytotoxicity was
assessed with the 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyl tetrazolium bromide
method, as previously
described.22 Serial
dilutions of samples to be tested were compared with a standard curve of
recombinant mouse TNF- and expressed as units per milliliter. One unit
per milliliter is the amount of TNF- that kills 50% of the cells. The
lower detection limit of the assay at the dilutions of the samples used was 1
U/mL.
Statistical Analysis
Data are expressed as means ± SEM.
Statistical analysis was performed by using the Statistical Package for the
Social Sciences (SPSS 11.0, Chicago, IL) and BMDP (BMDP Statistical Software,
Los Angeles, CA). Differences between groups were detected by 2-way analysis
of variance, with Kupffer-cell depletion and LPS-infusion as fixed factors.
p Values of <0.05 were considered significant.
|
RESULTS
|
|---|
CL2MDP Liposome Injection and the Hepatic Macrophage Population
Injection in the tail vein with CL2MDP liposomes resulted in
<1% positive ED2 cells per microscopic field (magnification 200x) in
both periportal and pericentral areas of the resected liver lobes. An almost
complete elimination of KCs was achieved. Results are shown in
Table I.
Hemodynamics and VR
Vital signs such as MAP, HR, and VR are given in
Figure 1 as means ± SEM.
Differences are detected for mean arterial pressure: CL2MDP-SAL
vs CL2MDP-LPS, p < 0.05 for 180 to 240
minutes; CON-LPS vs CL2MDP-LPS, p < 0.05 for
180 to 240 minutes; HR: CON-SAL vs CON-LPS, p < 0.05 for
150 to 240 minutes; CL2MDP-SAL vs CL2MDP-LPS,
p < 0.05 for 150 to 240 minutes; CON-LPS vs
CL2MDP-LPS, p < 0.05 for 240 minutes; VR: CON-SAL
vs CON-LPS, p < 0.05 for 90 to 240 minutes;
CL2MDP-SAL vs CL2MDP-LPS, p < 0.05
for 120 to 240 minutes.
View larger version (9K):
[in this window]
[in a new window]
|
FIG. 1. Hemodynamics and ventilatory rate. Vital signs such as mean arterial
pressures (MAP), heart rate (HR), and ventilatory rate (VR) are given as means
± SEM. Significances are indicated. Mean arterial pressure:
*CL2MDP-SAL vs CL2MDP-LPS, p < 0.05 for 180–240
min; #CON-LPS vs CL2MDP-LPS p < 0.05 for 180–240 min.
Heart rate: +CON-SAL vs CON-LPS, p < 0.05 for 150–240 min;
*CL2MDP-SAL vs CL2MDP-LPS, p < 0.05 for 150–240
min; #CON-LPS vs CL2MDP-LPS, p < 0.05 for 240 min. Ventilatory
rate: + CON-SAL vs CON-LPS, p < 0.05 for 90–240 min;
*CL2MDP-SAL vs CL2MDP-LPS, p < 0.05 for 120–240
min.
|
|
Blood Gas Analysis and Plasma Lactate
The results of blood gas analysis and plasma lactate are demonstrated in
Table II. Differences were
detected for PCO2: CON-SAL vs CON-LPS, p < .01
and CON-LPS vs CL2MDP-LPS, p < .001;
HCO3–: CON-SAL vs CON-LPS, p
< .01 and CL2MDP-SAL vs CL2MDP-LPS,
p < .01; lactate: CON-SAL vs CON-LPS, p <
.01, CL2MDP-SAL vs CL2MDP-LPS, p <
.01; and for CL2MDP-LPS vs CON-LPS, p <
.05.
TNF- and IL-1β mRNA Expression in the Liver
Values of liver TNF- and IL-1β mRNA expression are presented in
Figure 2A and
B, respectively. Differences are detected for CON-SAL
vs CON-LPS, p < .05 and for CL2MDP-SAL
vs CL2MDP-LPS, p < .05 and CON-SAL vs
CL2MDP-SAL, p < .05 in
Figure 2A.
TNF- and IL-1β mRNA Expression in the Lung
Values of lung TNF- and IL-1β mRNA expression are presented in
Figure 3A and
B, respectively. Differences are detected in A
for CON-SAL vs CON-LPS, p < .05; and for
CL2MDP-SAL vs CL2MDP-LPS, p < .05.
In B, CON-SAL vs CON-LPS, p < .05 and for
CON-LPS vs CL2MDP-LPS, p < .05.
TNF- and IL-1β mRNA Expression in the Kidney
Values of kidney TNF- and IL-1β mRNA expression are presented
in Figure 4A and
B, respectively. Differences are detected for CON-SAL
vs CON-LPS, p < .01; and for CL2MDP-SAL
vs CL2MDP-LPS, p < .05, in
Figure 4. In B,
CON-SAL vs CL2MDP-SAL, p < .01.
Plasma TNF-
Values of plasma TNF- are given in
Figure 5. A difference was
detected for CON-LPS vs CL2MDP-LPS 1 hour after the
infusion of LPS, p < .01.
Influx of Macrophages and PMNs in the Lung and Kidney
The influx of macrophages and PMNs in the lung and kidney are shown in
Table III. Differences were
detected for the lung: CON-SAL vs CON-LPS, p < .01; for
CL2MDP-SAL vs CL2MDP-LPS, p < .05;
for CL2MDP-SAL vs CL2MDP-LPS, p <
.05; and for CON-LPS vs CL2MDP-LPS, p < .01.
Differences were detected for the kidney: CON-SAL vs CON-LPS,
p < .01; for CON-SAL vs CL2MDP-SAL, p
< .01; and for CON-LPS vs CL2MDP-LPS, p <
.01.
|
DISCUSSION
|
|---|
The present study shows that KCs have an important function after PH.
After PH, liver regeneration occurs rapidly, resulting in a complete
recovery of hepatocyte mass. A sufficient mass of hepatocytes is required to
carry out immediate life-sustaining functions and successful regeneration to a
normal hepatocyte number for full recovery. The precise mechanism of this
regeneration is not fully understood; KCs are thought to play a major role in
this process. The KCs are anatomically juxtaposed with hepatocytes and release
various inflammatory mediators that are necessary for liver regeneration after
PH, but are also able to induce hepatocellular damage as a result of a local
inflammatory
response.9–11
We have previously shown that KCs have an preserving effect on the remnant
liver after
PH.12
A method to investigate the role of KCs after PH is to "physically
eliminate" KCs with the liposome encapsulated dichloromethylene
diphosphonate (CL2MDP) to determine the role of these cells as part
of the monocyte/macrophage
lineage.15 When
these liposomes are administered IV, they are largely ingested by KCs almost
exclusively through phagocytosis and are subsequently disrupted by lysosomal
phospholipase. In the process, CL2MDP is released in the cytoplasm
of macrophages, eventually killing these cells. The mechanism of cell death
after ingestion of CL2MDP liposomes is
apoptosis.15
Indeed, in Table I it is shown
that an almost complete elimination of KCs was achieved.
In this model a small dose of endotoxin was given to mimic a pneumoniae or
urinary tract, or wound infection, as commonly seen after PH in daily surgical
practice.
In Figure 1, it was shown
that PH in KC-depleted rats resulted in a lower mean arterial pressure, a
higher heart and VR after endotoxemia. These clinical derangements were
further substantiated with blood gas and lactate analysis
(Table II). All rats were able
to maintain pH in normal ranges. The KC-depleted rats after PH had the lowest
CO2 levels, confirming the high VR, and the highest levels of
lactate during endotoxemia. Oxygen levels were similar in all groups (data not
shown).
Cytokine gene expression of TNF- and IL-1β mRNA was measured in
hepatic, lung, and renal tissue and is shown in Figures
2,
3, and
4, respectively. Both
TNF- and IL-1β are inductors of systemic inflammation. An
endotoxin-induced increase in TNF- was observed in the liver (CON-SAL
vs CON-LPS), but when KCs were depleted, a significant reduction in
synthesis of TNF- was measured (CON-SAL vs
CL2MDP-SAL and CON-LPS vs CL2MDP-LPS,
Fig. 2). A similar pattern in
the synthesis of TNF- was observed in the lung and kidney (Figs.
3 and
4). For the synthesis of
IL-1β, only an endotoxin-mediated increase was detected for renal tissue
(Fig. 4). These results
indicate that a low dose of endotoxin predominantly induces mRNA synthesis of
TNF-, and when KCs are eliminated there is a reduction in TNF-
mRNA synthesis. This pattern was not seen in the synthesis of IL-1β.
Increased synthesis of TNF- mRNA results in higher plasma levels of
TNF-. Indeed, the highest plasma levels of TNF- were measured in
the endotoxin (CON-LPS)-treated rats compared with the KC-eliminated rats
(CL2MDP-LPS, Fig.
5). Note that just 1 hour after the injection of endotoxin,
TNF- plasma levels are maximal, after which plasma levels restore to
near normal (5–15 U/mL).
Macrophages and PMNs are recruited to sites of inflammation to release
several biologic active substances such as arachidonic acid, oxygen
metabolites, and serine proteases and exert their phagocytic capacities in
order to inactivate microorganisms. Macrophages and PMNs can either be
directly activated by endotoxin or by inflammatory mediators. TNF- or
IL-1β is a predominant example of these mediators and has potent
macrophage, monocyte, and polymorphonuclear chemotactic properties. Therefore,
influx of cells like macrophages and PMNs in, for instance, the lung and
kidney are parameters of the systemic inflammatory response. In
Table III, pulmonary and renal
influx of macrophages and PMNs is increased after an endotoxin challenge
(CON-SAL vs CON-LPS), but the highest influx was measured in
KC-depleted rats (CON-LPS vs CL2MDP-LPS), indicating a
higher systemic inflammatory response. Interestingly, elimination of KCs
increased influx of macrophages and PMNs when compared with controls,
indicating the important role of KCs as a part of the mononuclear phagocytic
system.
Briefly, endotoxemia in KC-depleted rats after PH resulted in hemodynamic,
ventilatory, and metabolic derangements and an increased systemic
inflammation. Although TNF- and IL-1β are major mediators of
systemic inflammation, the hemodynamic, ventilatory, and metabolic
derangements and increased systemic inflammation was not accompanied by
increased levels of TNF- and IL-1β. On the contrary, IL-1β
mRNA synthesis was not altered, and TNF- mRNA synthesis decreased after
KC depletion.
The results of the study show that rats with intact KC function after PH
have a better performance after a low-dose endotoxin challenge. The increased
systemic inflammatory response could not be explained by a higher cytokine
synthesis. Therefore, it is postulated that the better performance of rats
after an endotoxin challenge must be found in the KC itself. The
endotoxin-clearing capacity of KCs most likely plays a dominant role in this
process.
This is an interesting finding, but it contrasts with several reports of
deleterious effects of cytokine release by activated KCs. For instance, it was
demonstrated that a portocaval shunt prevented pancreatitis-induced lung
injury by bypassing the resident macrophages of the liver, thus preventing
activation of
KCs.23 In the same
model, a reduction in acute pancreatitis mortality was observed when KCs were
blocked using gadolinium
chloride.23
Blocking KCs with gadolinium chloride also prevented mortality in
hepatectomized rats given endotoxin, most likely by inhibiting superoxide
production by
KCs.24
There are, however, studies reporting other effects of activated KCs. In
KC-depleted cold-preserved rat livers, using CL2MDP liposomes,
there was no difference of ischemia and reperfusion
injury.25 Salkowski
et al26 have
described that KC depletion by CL2MDP liposomes resulted in reduced
cytokine gene expression, and rats treated with these liposomes had more
tissue damage after radiation than controls, which is in line with our
results.
Obviously, there is a discrepancy between the reports concerning the effect
of the activated KC, but there are some possible explanations. First, it seems
that the method of studying KC functioning is influential because most of the
reports using gadolinium chloride describe deleterious effects of the
activated KC. Gadolinium chloride blocks the cytokine release of KCs; however,
there is no information about the effect gadolinium chloride has on the
phagocytic capacity of the KC. Therefore, it is difficult to judge because the
balance between the cytotoxic and cytoprotective function of the KC is
disrupted, an effect that is not seen in the liposome-eliminating method.
Second, there are differences in experimental models and doses of noxious
substances (for instance, endotoxin), making comparisons difficult.
Because intact KC function is important to overcome endotoxin-related
hemodynamic, metabolic, and systemic inflammatory disturbances after PH, it is
advocated to minimize Kupffer-compromising perioperative strategies, such as
parenteral nutrition, in patients undergoing major liver
resection.27,28
Selective bowel decontamination in order to eliminate Gram-negative
microorganisms in patients undergoing liver resection might preserve KC,
eventually resulting in better outcome after PH.
In conclusion, KC-depleted rats have a better clinical performance, a
decreased cytokine release, and an increased systemic inflammatory response
after a low-dose endotoxin challenge after PH.
We thank Agnes Huijsman and Nico van Rooijen from the department of Cell
Biology and Immunology, Medical Faculty, Vrije Universiteit, Amsterdam, for
assistance in immunohistochemical assays and for providing CL2MDP
liposomes, respectively.
Major liver surgery in Kupffer cell–depleted rats result in a more
pronounced endotoxin-mediated systemic inflammation and decreased synthesis of
cytokines.
Received for publication August 18, 2004.
Accepted for publication October 14, 2004.
- Sitzmann JV, Greene PS. Perioperative predictors of morbidity
following hepatic resection for neoplasm: a multivariate analysis of a single
surgeon experience with 105 patients. Ann Surg.1994; 219:13
–17.[Web of Science][Medline]
[Order article via Infotrieve]
- Nolan JP. Endotoxin, RES function and liver injury.Hepatology.
1981;1:458
–465.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Bradfield JWB. Control of spillover: the importance of Kupffer-cell
function in clinical medicine. Lancet.1974; 2:883
–886.[Web of Science][Medline]
[Order article via Infotrieve]
- Boermeester MA, Straatsburg IH, Houdijk APJ, et al. Endotoxin and
interleukin-1 related hepatic inflammatory response promotes liver failure
after partial hepatectomy. Hepatology. 1995;22
:1499
–1506.[Web of Science][Medline]
[Order article via Infotrieve]
- Boermeester MA, Houdijk APJ, Meijer S, et al. Liver failure induces
a systemic inflammatory response: prevention by recombinant N-terminal
bactericidal/permeability-increasing protein. Am J Pathol.1995; 147:1428
–1440.[Abstract]
- Ramadori G, Armbrust T. Cytokines in the liver. Eur J
Gastroenterol Hepatol. 2001;13:777
–784.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Nakamitsu A, Hiyama E, Imamura Y, Matsuura Y, Yokoyama T. Kupffer
cell function in ischemic and nonischemic livers after hepatic partial
ischemia/reperfusion. Surg Today.2001; 31:140
–148.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- van Rooijen N, Kors N, van de Ende M, Dijkstra CD. Depletion and
repopulation of macrophages in spleen and liver of rat after intravenous
treatment with liposome-encapsulated dichloromethylene diphosphonate.Cell Tissue Res.
1990;260:215
–222.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Tiegs G, Wolter M, Wendel A. Tumor necrosis factor is a terminal
mediator in galactosamine/endotoxin induced hepatitis in mice. Biochem
Pharmacol. 1989;38:627
–631.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Czaja MJ, Xu J, Alt E. Prevention of carbon tetrachloride induced
rat liver injury by soluble tumor necrosis factor receptor.Gastroenterology.
1995;108:1849
–1854.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Beutler B, Milsark IW, Cerami AC. Passive immunisation against
cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin.Science.
1985;229:869
–871.[Abstract/Free Full Text]
- Prins HA, Meijer C, Nijveldt RJ, Wiezer S, van Leeuwen PAM. High
plasma levels of arginine and arginase in Kupffer cell depleted rats after
partial hepatectomy. J Hepatol.2000; 32:399
–405.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Higgins GM, Anderson RM. Experimental pathology of the liver, I:
restoration of the liver of the white rat following partial surgical removal.Arch Pathol.
1931;12:186
–202.[Web of Science]
- Shi J, Gilbert GE, Kokubo Y, Ohashi T. Role of the liver in
regulating numbers of circulating neutrophils. Blood.2001; 98:1226
–1230.[Abstract/Free Full Text]
- van Rooijen N, Sanders A. Liposome mediated depletion of
macrophages: mechanism of action, preparation of liposomes and applications.J Immunol Methods.1994; 174:83
–93.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Barbé E, Damoiseaux JGMC, Döpp EA, Dijkstra CD.
Characterization and expression of the antigen present on resident rat
macrophages recognized by monoclonal antibody ED2.Immunobiology.
1990;182:88
–99.[Web of Science][Medline]
[Order article via Infotrieve]
- Meijer C, Wiezer MJ, Diehl AM, et al. Kupffer cell depletion by
CL2MDP-liposomes alters hepatic cytokine expression and delays
liver regeneration after partial hepatectomy. Liver.2000; 20:66
–77.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Damoiseaux JGMC, Döpp EA, Calame W, Chao D, MacPherson GG,
Dijkstra CD. Rat macrophage lysosomal membrane antigen recognized by
monoclonal antibody ED1. Immunology.1994; 83:140
–147.[Web of Science][Medline]
[Order article via Infotrieve]
- Chomczynski P, Sacchi N. Single-step method of RNA isolation by
acid guanidium thiocyanate-phenol-chloroform extraction. Anal
Biochem. 1987;162:156
–159.[Web of Science][Medline]
[Order article via Infotrieve]
- Scotté M, Masson S, Lyoumi S, et al. Cytokine gene
expression in liver following minor or major hepatectomy in rat.Cytokine.
1997;9:859
–867.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Espevik T, Nissen-Meyer J. A highly sensitive cell line, WEHI 164
clone 13, for measuring cytotoxic factor/tumor necrosis factor from human
monocytes. J Immunol Methods.1986; 95:99
–105.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Hansen MB, Nielsen SE, Berg K. Re-examination and further
development of a precise and rapid dye method for measuring cell growth/cell
kill. J Immunol Methods. 1989;119
:203
–210.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Gloor B, Todd KE, Lane JS, Lewis MP, Reber HA. Hepatic Kupffer cell
blockade reduces mortality of acute hemorrhagic pancreatitis in mice. J
Gastrointest Surg. 1998;2:430
–435.[CrossRef][Medline]
[Order article via Infotrieve]
- Kono H, Fujii H, Matsuda M, Yamamoto M, Matsumoto Y. Gadolinium
chloride prevents mortality in hepatectomized rats given endotoxin. J
Surg Res. 2001;96:204
–210.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Reinders ME, van Wagensveld BA, van Gulik TM, et al. No attenuation
of ischemic and reperfusion injury in Kupffer cell-depleted, cold-preserved
rat livers. Transplantation.1997; 63:449
–454.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Salkowski CA, Neta R, Wynn TA, Strassmann G, Van Rooijen N, Vogel
SN. Effect of liposome-mediated macrophage depletion on LPS-induced cytokine
gene expression and radioprotection. J Immunol.1995; 155:3168
–3179.[Abstract]
- Iwai M, Cui TX, Kitamura H, Saito M, Shimazu T. Increased secretion
of tumour necrosis factor and interleukin 6 from isolated, perfused liver of
rats after partial hepatectomy. Cytokine.2001; 13:60
–64.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Lu CJ, Redmond D, Baggs RB, Schecter A, Gasiewicz TA. Growth and
hepatic composition in the guinea pig after long-term parenteral
hyperalimentation. Am J Physiol.1986; 251:R388
–R397.[Web of Science][Medline]
[Order article via Infotrieve]
Journal of Parenteral and Enteral Nutrition, Vol. 29, No. 1,
48-55 (2005)
DOI: 10.1177/014860710502900148
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
|
|
Top
MATERIALS AND METHODS
RESULTS
