1 Department of Medicine II, The generation of reactive oxygen species
(ROS) by activated Kupffer cells contributes to liver injury following
liver preservation, shock, or endotoxemia. Pharmacological
interventions to protect liver cells against this inflammatory response
of Kupffer cells have not yet been established. Atrial natriuretic
peptide (ANP) protects the liver against ischemia-reperfusion
injury, suggesting a possible modulation of Kupffer cell-mediated
cytotoxicity. Therefore, we investigated the mechanism of
cytoprotection by ANP during Kupffer cell activation in perfused rat
livers of male Sprague-Dawley rats. Activation of Kupffer cells by
zymosan (150 µg/ml) resulted in considerable cell damage, as assessed
by the sinusoidal release of lactate dehydrogenase and purine
nucleoside phosphorylase. Cell damage was almost completely prevented
by superoxide dismutase (50 U/ml) and catalase (150 U/ml),
indicating ROS-related liver injury. ANP (200 nM) reduced Kupffer
cell-induced injury via the guanylyl cyclase-coupled A receptor (GCA
receptor) and cGMP: mRNA expression of the GCA receptor was found in
hepatocytes, endothelial cells, and Kupffer cells, and the cGMP analog
8-bromo-cGMP (8-BrcGMP; 50 µM) was as potent as ANP in protecting
from zymosan-induced cell damage. ANP and 8-BrcGMP significantly
attenuated the prolonged increase of hepatic vascular resistance when
Kupffer cell activation occurred. Furthermore, both compounds reduced
oxidative cell damage following infusion of
H2O2
(500 µM). In contrast, superoxide anion formation of isolated Kupffer
cells was not affected by ANP and only moderately reduced by 8-BrcGMP.
In conclusion, ANP protects the liver against Kupffer cell-related
oxidant stress. This hormonal protection is mediated via the GCA
receptor and cGMP, suggesting that the cGMP receptor plays a critical
role in controlling oxidative cell damage. Thus ANP signaling should be
considered as a new pharmacological target for protecting liver cells
against the inflammatory response of activated Kupffer cells without
eliminating the vital host defense function of these cells.
guanosine 3',5'-cyclic monophosphate; cytoprotection; liver injury; liver perfusion; reactive oxygen species
ISCHEMIA-REPERFUSION INJURY is an important determinant
for the success of liver transplantation. This injury contributes to
primary nonfunction, dysfunction, and nonanastomotic biliary stenosis
and is therefore pivotal for morbidity and mortality after liver
transplantation (26). Thus better protection against ischemia-reperfusion injury is urgently needed.
Several pathomechanisms contribute to ischemia-reperfusion
injury of the liver. Lack of oxygen during ischemia induces
depletion of ATP, followed by a deterioration of intracellular
Ca2+ and
Na+ homeostasis (9, 18) and the
activation of cytotoxic enzymes such as proteases (17). Additional
damage occurs during reperfusion. Reactive oxygen species (ROS) have
been implicated in the pathogenesis of hepatic reperfusion injury (15,
20). Several studies revealed that activated Kupffer cells contribute
to postischemic oxidant stress during initial reperfusion (8, 21).
Furthermore, the activation of Kupffer cells induces a complex network
of cytokines, which participates in sinusoidal accumulation of
granulocytes and microcirculatory failure (10, 12, 23). Kupffer cell activation and the subsequent vascular inflammation also play a central
role in liver injury induced by endotoxin (23, 32). This potent
activator of Kupffer cells translocates across the gut into donor
organs and causes graft failure after liver transplantation (35, 40).
Thus pharmacological interventions directed toward a reduction of
Kupffer cell-related cell damage may protect the liver against
reperfusion injury; however, these interventions have not yet been established.
Recently, we have shown that atrial natriuretic peptide (ANP)
protects the liver against ischemia-reperfusion injury (6, 19).
This circulating hormone released by the heart in response to volume
expansion also preserves kidney function after renal ischemia
and reperfusion (34, 37). The mechanisms of ANP-mediated cytoprotection
remain to be elucidated and may provide insight into signal
transduction processes as possible targets of pharmacological intervention. ANP has received attention mainly for its vasodilating properties (4, 27). However, recent evidence shows that ANP has an
impact on other biological functions, e.g., on the immune system (43,
44). In this respect, an influence of ANP on macrophage activation has
recently been observed (24). On the basis of these findings, a possible
modulation of Kupffer cells, the resident macrophages of the liver, by
ANP could be hypothesized. Alternatively, ANP might counteract
consequences of Kupffer cell activation, such as liver cell damage by
ROS. Thus potential hazards of other protective approaches interfering
with the inflammatory response, such as suppression of the Kupffer
cell-related host defense, would be avoided.
Two major subtypes of ANP receptors have been characterized and are
present in the liver (33, 41). The ANP A receptor is coupled to
particulate guanylyl cyclase (the GCA receptor) and thus is responsible
for cGMP-mediated ANP effects, in particular vasodilation and decreased
cytosolic free Ca2+ (27). The ANP
C receptor functions predominantly as a clearance receptor and lacks
guanylyl cyclase activity but may decrease adenylate cyclase activity
(27). The GCA receptor has been demonstrated in isolated hepatocytes
(46), but, until now, it remains unclear whether this receptor is also
expressed in nonparenchymal liver cells.
Therefore, the aim of our investigation was to study the protective
effects of ANP on Kupffer cell-derived injury in the perfused rat
liver. This model allows the selective activation of Kupffer cells by
zymosan (cell wall particles from yeast) (14) without concomitant
effects from neutrophils and extrahepatic macrophages. The sinusoidal
release of lactate dehydrogenase (LDH) and purine nucleoside
phosphorylase (PNP) were determined as parameters of cell damage. To
characterize the mechanisms of ANP action, we investigated expression
of the GCA receptor in parenchymal and nonparenchymal liver cells and
the effects of its second messenger cGMP. Furthermore, direct ANP
effects on reactive oxygen formation were investigated in isolated
Kupffer cells.
Animals and materials.
Male Sprague-Dawley rats were purchased from Sawo (Kieslegg, Germany)
and housed in a temperature- and humidity-controlled room under a
constant 12:12-h light-dark cycle. The animals had free access to water
and rat chow (standard diet, Altromin 1314, Lage, Germany). All
experiments were performed with nonfasting rats weighing 250-300
g. The animals received humane care in compliance with guidelines of
the local animal welfare committee.
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
Isolated perfused rat liver.
Rats were anesthetized with pentobarbital sodium (50 mg/kg body wt ip).
After incision of the abdominal wall, the portal vein was cannulated
with a 14-gauge Teflon intravenous catheter and the liver was perfused
at a constant flow rate of 3.5 ml · min1 · g
liver
1 with Krebs-Henseleit
buffer (38). The inferior vena cava was then cannulated via the right
atrium and ligated above the right renal vein. After the bile duct was
cannulated with PE-10 tubing, the liver was dissected free and
transferred to a perfusion chamber.
Experimental protocol. Eight groups of rat livers were studied. Groups 1-4 were subjected to zymosan (150 µg/ml) as follows. For group 1, zymosan was administered from minute 40 to 46 after perfusion was started (n = 6); for group 2, ANP (2, 20, or 200 nM) was administered from minute 30 to 50 and zymosan from minute 40 to 46 (n = 4); for group 3, SOD (50 U/ml) and catalase (150 mU/ml) were administered from minute 30 to 50 and zymosan from minute 40 to 46 (n = 4); and for group 4, 8-BrcGMP (50 µM) was administered from minute 30 to 50 and zymosan from minute 40 to 46 (n = 4).
Groups 5-8 underwent perfusion with H2O2 as follows. Group 5 rats were continuously perfused with Krebs-Henseleit buffer for 100 min (n = 6); for group 6, H2O2 (500 µM) was administered from minute 30 to 45 after perfusion was started (n = 5); for group 7, ANP (200 nM) was given from minute 10 to 50 of perfusion and H2O2 (500 µM) from minute 30 to 45 (n = 4); for group 8, 8-BrcGMP (50 µM) was administered from minute 10 to 50 and H2O2 (500 µM) from minute 30 to 45 (n = 4). Rat ANP, 8-BrcGMP, SOD, catalase, and H2O2 were dissolved in sodium chloride (0.9%). Stock solutions were infused into the portal inflow of the perfusion system by microinfusion pumps. Zymosan suspensions were kept at 95°C for 30 min to destroy endogenous phospholipase A2 activity (14). Zymosan suspensions were then diluted in Krebs-Henseleit buffer, yielding a final concentration of 150 µg/ml.Isolation of parenchymal and nonparenchymal liver cells. Cells were isolated from rats treated for 3 h with 2 mg/kg Salmonella enteritidis endotoxin or 1 ml/kg saline. Hepatocytes were isolated after collagenase digestion, and hepatic endothelial cells and Kupffer cells were separated by centrifugal elutriation as described in detail (22). Each cell fraction was repeatedly washed with Hanks' balanced salt solution (HBSS) and was >95% pure as assessed by morphology, peroxidase staining, and superoxide formation. Cell viability for each fraction was >90% for hepatocytes and >95% for Kupffer cells and endothelial cells as determined by trypan blue exclusion. Cells were used for either superoxide measurements (Kupffer cells) or total RNA isolation using the guanidinium thiocyanate method as described in detail (16).
Expression of natriuretic peptide receptors. mRNA was isolated by adsorption of total RNA to oligo(dT) magnetic beads (Promega) and quantified by ultraviolet adsorption. mRNA was reverse transcribed with avian myeloblastosis virus RT and used for PCR (24, 41). Amplification with a primer specific for the GCA receptor was performed as described elsewhere (42). Oligonucleotides used for PCR amplification had the following sequences: GCA receptor gene (rat) sense primer, 5'-AAGCTGATAATCCTGAGTACT-3'; antisense primer, 5'-TTGCAGGCTGGGTCCTCATTGTCA-3' (42).
Amplification products were separated by agarose gel electrophoresis and stained with ethidium bromide. As control for possible contaminations, mRNA instead of cDNA was amplified in parallel and no DNA bands were visible at electrophoresis.Analytic methods. Sinusoidal efflux rates of LDH and PNP were measured as indexes of liver cell damage (36, 38). The activity of LDH in the perfusate was analyzed according to a standard test (2). PNP activity was determined by the xanthine oxidase-coupled formation of uric acid at 293 nM (36).
Superoxide anion formation of isolated Kupffer cells was measured by ferricytochrome c reduction (22). Approximately 1.0 × 106 cells in HBSS containing 50 µM ferricytochrome c were plated on six-well culture plates in the absence or presence of SOD (500 U/ml). After a preincubation period of 20 min with or without 200 nM ANP or 50 µM 8-BrcGMP, Kupffer cells were activated by opsonized zymosan (150 µg/ml). The cell suspension was then incubated at 37°C for 60 min in a humidified environment containing 5% CO2. The amount of SOD-inhibitable ferricytochrome c reduction was measured with a molecular extinction coefficient of 21.1 mmol · lStatistics. All data are expressed as means ± SD. Statistical significance between the control group and a treated group was determined with the paired or unpaired Student's t-test. Comparisons between multiple groups were performed with one-way ANOVA followed by Bonferroni t-test. P < 0.05 was considered significant.
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RESULTS |
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Kupffer cell-induced liver injury.
Kupffer cells of isolated perfused rat livers were activated by a 6-min
infusion of zymosan (150 µg/ml), which is taken up by Kupffer cells
but not by hepatocytes or endothelial cells (14). Liver injury was
assessed from sinusoidal efflux of LDH and PNP. During zymosan
infusion, LDH and PNP efflux increased only slightly and then returned
to basal values. Forty minutes after zymosan infusion was started, LDH
and PNP efflux markedly increased (P < 0.05), reaching 56 ± 25 and 6.4 ± 3.4 mU · min1 · g
liver
1 at the end of
perfusion. In contrast, untreated livers showed LDH and PNP efflux
rates of only 4 ± 2 and 0.2 ± 0.1 mU · min
1 · g
liver
1, respectively, after
100 min of perfusion. Thus considerable cell damage was induced by
activation of Kupffer cells.
|
|
|
Hemodynamic effects of Kupffer cell activation.
During zymosan infusion, portal pressure increased transiently from 4.0 ± 0.2 to 18.8 ± 2.8 cmH2O.
When zymosan administration was terminated, portal pressure declined
rapidly but remained elevated above baseline levels (6.6 ± 0.7 cmH2O,
P < 0.05) (Fig. 4). These results indicate a prolonged
deterioration of the hepatic circulation after Kupffer cell activation.
Initial increase of portal pressure was not affected by pretreatment
with 200 nM ANP, but, during further perfusion, portal pressure
returned to baseline (4.0 ± 0.4 cmH2O) (Fig. 4). Similar
influences on the zymosan-induced increase of portal pressure were
observed with 20 nM ANP (4.6 ± 1.1 cmH2O). In contrast, 2 nM ANP
showed no hemodynamic effects. The hemodynamic effects of 20 and 200 nM
ANP were mimicked by 8-BrcGMP (50 µM) (Fig. 4), suggesting a GCA
receptor-cGMP-mediated attenuation of the prolonged increase of
vascular resistance induced by activated Kupffer cells.
|
GCA receptor expression in parenchymal and nonparenchymal liver
cells.
Hepatocytes, Kupffer cells, and endothelial cells were isolated from
untreated livers by enzymatic digestion and centrifugal elutriation.
After reverse transcription of mRNA, 200 ng of cDNA were amplified with
a specific primer of the GCA receptor. Specific transcripts of the GCA
receptor were found in hepatocytes, Kupffer cells, and endothelial
cells (Fig. 5). These findings
are in accordance with the earlier described particulate guanylyl
cyclase activity in hepatocytes and moreover show for the first time
expression of the GCA receptor in nonparenchymal liver cells.
|
Effect of ANP on O2·
generation of isolated Kupffer cells.
The marked attenuation of Kupffer cell-induced liver injury by ANP
suggests a reduction of ROS production or of ROS-related cell damage by
activated Kupffer cells. To test the first hypothesis, the influence of
ANP on O
2· generation of isolated
Kupffer cells was investigated. In agreement with earlier studies by
Bautista et al. (1), basal O
2· production of Kupffer cells from lipopolysaccharide-treated rats was
1.37 ± 0.25 and increased to 3.58 ± 0.56 nmol · h
1 · 106
cells
1
(P < 0.05) after administration of
opsonized zymosan (final concentration of 150 µg/ml). Preincubation
of Kupffer cells with 200 nM ANP for 20 min reduced basal and
zymosan-stimulated O
2· release by
15 and 18%, respectively, which was not significant (P > 0.05). Treatment
with 50 µM 8-BrcGMP resulted in a moderate attenuation of
O
2· formations by 28 and 36%,
respectively (P < 0.05).
Effect of ANP on
H2O2-induced
liver damage.
The lack of effect of ANP and the only moderate reduction of
O2· release of isolated Kupffer
cells by 8-BrcGMP suggest ANP-mediated mechanisms of protection against consequences of increased ROS formation. This hypothesis was tested by
infusion of 500 µM
H2O2
for 15 min. During
H2O2
infusion, sinusoidal efflux of LDH and PNP increased to a maximum of
559 ± 151 and 8.3 ± 1.1 mU · min
1 · g
liver
1, respectively. ANP
significantly reduced the
H2O2-induced
efflux of LDH to 272 ± 46 and of PNP to 3.2 ± 1.2 mU · min
1 · g
liver
1 (Fig.
6). Similar but gradually smaller
influences on
H2O2-induced cell damage were observed with 50 µM 8-BrcGMP (Fig. 6).
|
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DISCUSSION |
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Recently, protection of the kidney as well as the liver against ischemia-reperfusion damage by ANP has been reported (6, 19, 34, 37). Recent data show an effect of ANP on macrophage activation (24). Because activation of Kupffer cells plays a key role in reperfusion injury of the liver (8, 21), modulation of Kupffer cell-related cell damage might be an additional mechanism of ANP-mediated hepatoprotection. We therefore studied the effect of ANP on Kupffer cell-derived injury of the perfused rat liver. This model allows the selective activation of Kupffer cells by phagozytosable particles such as zymosan (14) without concomitant effects from activated neutrophils and extrahepatic macrophages. Using this approach, we propose a novel concept of hepatoprotection through ANP signaling via the GCA receptor: protection of liver cells against Kupffer cell-induced injury without elimination of the vital function of Kupffer cells in host defense.
Liver injury by activated Kupffer cells.
Activation of Kupffer cells in vivo induces a complex network of
cytokines accompanied by vascular inflammation (10, 12, 23).
Furthermore, there is evidence for a pivotal role of ROS in the complex
relation of these pathophysiological events. Several studies revealed a
relevant vascular oxidant stress by activated Kupffer cells, which
contributes to reperfusion injury (8, 15, 20, 21). Our experiments
support this hypothesis. The selective activation of Kupffer cells in
the perfused rat liver by zymosan resulted in a severalfold increase of
sinusoidal LDH and PNP efflux, indicating considerable cell damage.
Treatment with SOD and catalase reduced the zymosan-stimulated efflux
of LDH and PNP by ~70%. Because SOD and catalase selectively
detoxify O2· and
H2O2,
their protective effects indicate ROS-mediated liver cell damage by
activated Kupffer cells. Recently, it has been shown that ROS may
induce microcirculatory failure due to sinusoidal leukostasis (25, 30).
Because livers were perfused with a leukocyte-free buffer in our
experiments, other mechanisms of ROS-mediated liver cell damage must be
proposed. These imply the initiation of a cascade of reactions by
O
2· and
H2O2,
which induce lipid peroxidation and signal transduction via
redox-sensitive transcription factors such as nuclear transcription factor-
B (16, 20).
Protective effects of ANP. Treatment of livers with ANP reduced cellular damage, as indicated by a decrease of the sinusoidal efflux of LDH and PNP. The concentration of ANP was important for the protection: 200 nM ANP significantly reduced both LDH and PNP efflux rates; however, 20 nM ANP affected only LDH efflux, whereas 2 nM ANP influenced neither LDH nor PNP efflux. These results are in accordance with observations in models of ischemia-reperfusion injury of the liver and kidney. In these studies, reduction of cell damage was concentration dependent and only seen with ANP concentrations of 200 and 300 nM (6, 34). Recent investigations showed 60-fold higher activity of PNP in hepatocytes than in endothelial cells (7). Thus reduction of sinusoidal PNP release by ANP most likely indicates protection of hepatocytes. This contention is supported by the histological finding that ANP protects hepatocytes, but not nonparenchymal liver cells, against ischemia-reperfusion injury (19).
Receptors and second messenger of ANP-mediated protection. Biological actions of ANP are mediated by different receptors in the cell membrane: the GCA receptor and the C receptor (27). Stimulation of the GCA receptor increases intracellular cGMP, whereas the C receptor is thought to function as a clearance receptor (27). Treatment of the liver with the cGMP analog 8-BrcGMP protected livers from Kupffer cell-related damage in a fashion similar to ANP. These results suggest a GCA receptor and cGMP-mediated hepatoprotection by ANP. With the use of PCR, we demonstrated expression of the GCA receptor in hepatocytes, sinusoidal endothelial cells, and Kupffer cells. With the use of this highly sensitive PCR technique, it has to be considered that transcripts might originate from impurities of the cell fractions. However, there is additional evidence for a presence of the GCA receptor on the different cells investigated. First, studies with isolated hepatocytes have shown that ANP elicits a dose-dependent increase of cGMP, the second messenger of GCA receptor stimulation (45). Second, the GCA receptor has been demonstrated on many different preparations of endothelial cells (29). Furthermore, GCA receptor expression seems likely because ANP-binding sites have been demonstrated on sinusoidal endothelial cells (3). Third, GCA receptor expression in Kupffer cells is supported by results obtained in macrophage cell lines: the production of nitric oxide was significantly reduced by ANP and cGMP analogs (22). Consequently, protective ANP effects could be mediated by the GCA receptor of parenchymal and nonparenchymal cells of the liver.
Mechanism of ANP-mediated protection. During zymosan infusion, portal pressure increased by 400% because of the release of vasoconstrictors such as prostaglandins and leukotrienes (13). When zymosan administration was terminated, portal pressure declined rapidly but did not return to baseline after 1 h. Thus long-lasting deteriorations of the hepatic circulation could contribute to cell damage. ANP, a potent vasodilator in the liver (4), significantly attenuated the prolonged increase of portal pressure. Similar hemodynamic effects were observed with 8-BrcGMP, suggesting a GCA receptor and cGMP-mediated vasodilation by ANP. Thus protection by ANP could be linked to its vasodilating properties, which may counteract microcirculatory failure after Kupffer cell activation.
As discussed above, ROS release into sinusoids seems to be the major mechanism of cell damage after Kupffer cell activation in the perfused rat liver. Therefore, questions arise whether ANP modulates ROS production or their consequences. Recently, it has been shown that ANP and cGMP analogs can inhibit nitric oxide production of macrophages (24). This may reduce the production of highly toxic peroxynitrite, which is formed by the reaction of O ![]() |
ACKNOWLEDGEMENTS |
---|
We thank U. Rüberg and R. Woller for excellent technical assistance and U. Keller for careful preparation of the manuscript. C. Lerch (Novabiochem, Läufelfingen, Switzerland) is thanked for technical support.
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FOOTNOTES |
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This work was supported by grants from the Deutsche Forschungsgemeinschaft (GE576/14-1) and the Friedrich Bauer Stiftung and the Münchener Medizinische Wochenschrift.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. Bilzer, Dept. of Medicine II, Klinikum Grosshadern, Univ. of Munich, 81377 Munich, Germany.
Received 3 June 1998; accepted in final form 7 December 1998.
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