Departments of 1 Molecular and Cellular Physiology, 4 Pediatrics, and 5 Medicine, LSU Health Sciences Center, Shreveport, Louisiana 71130; 2 DNAX Research Institute, Palo Alto, California 94304; 3 National Jewish Medical and Research Center, Denver 80206; and 6 Webb-Waring Institute, University of Colorado Health Sciences Center, Denver, Colorado 80262
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ABSTRACT |
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The objective of this study was to
define the relationship among Kupffer cells, O expression in the pathophysiology of
postischemic liver injury following short and long periods of
ischemia. Using different forms of superoxide dismutase with
varying circulating half-lives, a monoclonal antibody directed against
mouse TNF-
, and NADPH oxidase-deficient mice, we found that 45 or 90 min of partial (70%) liver ischemia and 6 h of
reperfusion (I/R) produced time-dependent increases in liver injury and
TNF-
expression in the absence of neutrophil infiltration.
Furthermore, we observed that hepatocellular injury induced by short
periods of ischemia were not dependent on formation of TNF-
but were dependent on Kupffer cells and NADPH oxidase-independent
production of O
expression. We conclude that the sources for
O
in the pathophysiology of I/R-induced hepatocellular injury differ
depending on the duration of ischemia.
transplantation; leukocytes; reactive oxygen species; proinflammatory cytokines; NADPH oxidase
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INTRODUCTION |
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INTERRUPTION OF BLOOD
FLOW to the liver is an unavoidable consequence of liver
transplantation and resectional surgery (7). There is a
growing body of experimental and clinical data to suggest that the
ischemia and reperfusion (I/R) induced by these surgical procedures or pathophysiological events injures the liver and may
ultimately lead to tissue dysfunction and possibly liver failure (25). Recent evidence suggests that I/R-induced liver
injury occurs in two distinct phases, consisting of an acute phase
occurring within the first 6 h of reperfusion followed by a later,
subacute phase occurring from 6 to 24 h after ischemia
(29). The acute phase is characterized by the
polymorphonuclear leukocyte (PMN)-independent activation of resident
Kupffer cells, resulting in enhanced production of reactive oxygen
species (ROS) in association with alterations in the redox state of the
tissue in favor of a more oxidative environment (10, 19,
46). Historically, enhanced ROS production has been thought to
injure tissue by virtue of its ability to degrade membrane lipids
and/or proteins. However, more recent studies suggest that oxidative
degradation of biomolecules is not produced at a time or is produced in
insufficient amounts to account for I/R-induced liver injury
(34). In fact, it is becoming increasingly appreciated
that ROS may mediate the early I/R-induced liver injury via their
ability to enhance the expression of certain redox-sensitive genes
known to be important in promoting hepatocellular injury. For example,
several lines of evidence implicate I/R-induced ROS production in
mediating hepatocellular injury by activating the NF-B and activator
protein-1-dependent expression of certain cytokines known to be
involved in the pathophysiology of I/R-induced injury (50,
51). Indeed, Kupffer cell- and/or hepatocyte-derived expression
of TNF-
, IL-1
, and IL-12 have been implicated as important
mediators of reperfusion injury in the liver (3, 28, 42).
In contrast, the late, subacute phase of I/R injury has been shown to be a PMN-dependent process in which I/R-induced ROS generation is associated with cytokine and chemokine expression (16, 33). There is good evidence to suggest that these inflammatory mediators promote the invasion of PMNs into the interstitium via the upregulation of adhesion molecules and formation of chemotactic gradients (33, 43). Adherent PMNs become metabolically activated and transmigrate through the sinusoidal and microvascular endothelial cells to the underlying hepatocytes, where they generate additional reactive oxygen metabolites in conjunction with the release of extracellular matrix-degrading enzymes such as collagenase and matrix metalloproteases (17, 19, 20). The net result is an amplification of the acute responses resulting in extensive inflammatory tissue injury.
Although several different studies have demonstrated the protective
effects of antioxidant intervention in I/R-induced liver injury
(7, 15, 37, 47, 49, 50), the identity of the specific
reactive species, the sources of these oxidants and free radicals, and
mechanisms by which these reactive oxygen metabolites promote
hepatocellular injury have yet to be defined. Indeed, the use of
low-molecular-weight ROS scavengers and/or enzymatic antioxidants has
proven problematic given their nonspecific nature and/or short
circulating half-life (8). It has been proposed that ROS
may be generated during the early and late phases of liver I/R by
xanthine oxidase (XO), mitochondrial respiration, and/or Kupffer cell-
and PMN-associated NADPH oxidase (16, 26). Although
different investigators have implicated mitochondrial metabolism or XO
as potential sources for ROS generation in the postischemic
liver, there has been little evidence concerning the role of NADPH
oxidase. This multimeric O
Because the duration of ischemia imposed by the different
surgical procedures varies considerably, it is reasonable to assume that the mechanisms responsible for postischemic liver injury may be quite different (7, 15). Thus we wished to define the relationship among Kupffer cells, O expression in postischemic liver injury following
short and long periods of ischemia.
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MATERIALS AND METHODS |
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Animals.
Wild-type C57BL/6 mice (18-24 g) were purchased from Harlan
Sprague Dawley, and mice genetically deficient in the
gp91phox subunit of NADPH oxidase (gp91/
)
were obtained from Jackson Laboratories (Bar Harbor, ME) and generated
as described previously (39). All animals were
maintained on a standard laboratory diet with free access to food and
water until the time of the experiment. All experimental procedures complied with the Guide for the Care and Use of Laboratory
Animals (revised 1996), approved by the Council of The American
Physiological Society, and with federal and state regulations.
Animal model of partial hepatic I/R.
Fasted (16-18 h) male mice were anesthetized with a single
intramuscular injection of ketamine (150 mg/kg) and xylazine (7.5 mg/kg), and a laparotomy was performed. The intestines were gently lifted from the body cavity to access the liver and portal vein. The
quadrate lobe was subsequently dissected from the left lateral lobe to
further expose the portal triad. An atraumatic clip was placed across
the portal vein, hepatic artery, and bile duct just above the branch of
the right lateral lobe. The intestines were placed back inside the
cavity, and 500 µl of 10 U/ml heparinized saline was added to the
peritoneal cavity. The animals were then placed under a heating lamp
for 45 or 90 min. Sham-operated animals received laparotomy without
vessel occlusion. After ischemia or sham laparotomy, the
peritoneal cavity was sutured shut, and animals were allowed to recover
and livers to reperfuse for 6 h. Following this period, serum and
tissue were collected from each animal and frozen at 70°C for
subsequent liver enzyme and cytokine determinations, histopathological
assessment, and myeloperoxidase (MPO) content.
Serum alanine aminotransferase measurements. Serum levels of alanine aminotransferase (ALT) were measured from all animals subjected to I/R. Blood was taken from the inferior vena cava following 45 or 90 min of ischemia and 6 h of reperfusion and placed in a serum separator tube (Becton Dickson, Franklin Lakes, NJ). The samples were allowed to clot on ice for ~10 min, after which they were centrifuged at 4,000 g for 10 min. Serum was then collected, and ALT was measured by using a kit from Sigma (St. Louis, MO). Data are presented as units per liter at 37°C.
Histopathology. Liver tissue was fixed in ice-cold 10% phosphate-buffered formalin (Fisher Scientific, Fair Lawn, NJ) for 24 h at 4°C. The tissue was subsequently partially dehydrated with ethanol and embedded in JB4 plastic mounting media (Polysciences, Warrington PA). Five-micrometer sections were cut and stained with hematoxylin and eosin. Following staining, the sections were scored in a blinded fashion as previously described (12).
MPO measurements.
PMN infiltration was assessed by measurement of hepatic MPO activity
following 45 or 90 min of ischemia and 6 h of reperfusion by using an established method (27). Briefly, ~100 mg of
liver tissue was homogenized in 2 ml of sodium phosphate buffer (pH 7.4). Samples were then centrifuged at 3,000 g for 20 min at
4°C. Pellets were resuspended in 5 volumes of buffer containing EDTA and 0.5% (wt/vol) hexadecyltrimethylammonium bromide (Sigma). Samples
were frozen at 20°C, followed by thawing and then sonication on
ice. To inactivate any endogenous catalase, samples were heated for
2 h at 60°C. Samples were then centrifuged at 3,000 g
at 4°C, and the supernatant was used for MPO measurement. MPO was
quantified by measuring the MPO-catalyzed,
H2O2-dependent oxidation of
3,3',5,5'-tetramethylbenzidene (Sigma) at 655 nm. MPO content was
expressed as optical density (OD) at 655 nm after termination of the
reaction with ice-cold 200 mM acetic acid (pH 3.0).
Serum cytokine levels.
Serum levels of TNF- were quantified by using an ELISA kit according
to the manufacturer's specifications (Quantikine M TNF-
; R&D
Systems, Abingdon, UK). Serum was collected as described for the ALT
measurements and was stored at
80°C until measurements could be
performed. Data were then presented as picograms per milliliter of
serum TNF-
.
Antioxidant and antibody studies.
Mice were given a bolus injection in the tail vein of AEOL-10150 (3 mg/kg iv; Aeolus Pharmaceuticals). A mouse was euthanized at 1, 2, and
6 h after injection, and blood was collected in heparin tubes by
cardiac puncture. Plasma was analyzed for AEOL-10150 by HPLC-UV
detection as previously described (21). The plasma half-life was estimated by using a single exponential term model
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Inactivation of Kupffer cells.
Wild-type or gp91/
mice were treated with 10 mg/kg ip
of GdCl3 or vehicle (0.9% NaCl) 24 h before the
initiation of I/R, as previously described (36). Serum and
tissue were subsequently collected following 6 h of reperfusion
and analyzed as described above.
Statistical analysis. All values are presented as means ± SE. Data were analyzed by using the Students t-test or analysis of variance, and significance was set at P < 0.05.
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RESULTS |
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Tissue injury and TNF- expression following different periods of
ischemia.
Figure 1 demonstrates that 45 or 90 min
of ischemia followed by varying times of reperfusion produces
significant, time-dependent increases in serum ALT levels. Doubling the
duration of ischemia from 45 to 90 min produced an eightfold
increase in tissue injury as assessed by serum ALT at 6 h after
ischemia. Histopathological evaluation of the livers revealed
extensive hepatocellular necrosis in the absence of significant PMN
infiltration, which was consistent with the acute phase of liver injury
(Fig. 2). Coincident with liver injury,
we observed significant elevations in serum protein levels of TNF-
following 45 or 90 min of ischemia and 6 h of reperfusion
(Fig. 3). Figure
4 demonstrates that pretreatment of mice
with a single injection of TNF-
monoclonal antibody 15 min before
ischemia attenuated I/R-induced liver injury following 90 but
not 45 min of ischemia and 6 h of reperfusion.
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O
generation, and postischemic liver injury.
Previous investigations have identified ROS as important mediators of
reperfusion injury in the liver (47, 49). To assess the
role that O
following 45 or 90 min
of ischemia (Fig. 6).
Interestingly, native MnSOD administration was not effective at
reducing serum levels of TNF-
following either period of
ischemia, suggesting that its protective effect may be
independent of TNF-
generation (Fig. 6). Although AEOL-10150
administration showed a trend toward inhibition of TNF-
production,
these differences were also not statistically different compared with
vehicle-treated controls (Fig. 6).
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NADPH oxidase and hepatocellular injury.
Having established that O/
mice were
protected by ~50% from the I/R-induced liver injury following 90 but
not 45 min of ischemia as assessed by serum ALT. These data
suggest that extended periods of ischemia may be required for
the activation of this complex in Kupffer cells and/or sinusoidal and
microvascular endothelial cells and that this complex contributes to
approximately half of the O
at both 45 and 90 min of ischemia (Fig.
8).
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Role of Kupffer cells in postischemic injury following
different periods of ischemia.
Several different studies have implicated Kupffer cells as important
effector cells in the pathophysiology of postischemic liver
injury via their ability to elaborate potentially injurious ROS and
cytokines (14, 19, 41). However, few studies have systematically evaluated the importance of these resident phagocytes following different durations of ischemia within the same
model. Therefore, we examined the role of Kupffer cells following 45 or
90 min of ischemia and 6 h of reperfusion. We found that
inactivation of Kupffer cell function by pretreatment of mice with 10 mg/kg of GdCl3 24 h before the induction of
ischemia resulted in dramatic inhibition (80%) of I/R-induced
injury following 45 min of ischemia and 6 h of reperfusion
(Fig. 9). This same protocol reduced
liver injury by only 45% following 90 min of ischemia and
6 h of reperfusion. (Fig. 9). Because we and others (3,
40) have demonstrated that TNF- is responsible for
some of the I/R-induced hepatocellular injury, coupled with the fact
that Kupffer cells are well-known sources of this potentially injurious
cytokine (14), we investigated how Kupffer cell
inactivation affected cytokine expression following I/R. Figure
10 shows that inactivation of Kupffer
cell function by pretreatment with GdCl3 decreased
I/R-induced TNF-
release following both 45 and 90 min of
ischemia. In the final series of experiments, we assessed the
NADPH oxidase-independent effects of Kupffer cells in our model of
liver I/R by inactivating Kupffer cells in gp91
/
mice
by using GdCl3. We found that Kupffer cell inactivation attenuated I/R-induced liver injury following 90 min of
ischemia and 6 h of reperfusion by ~60% compared with
gp91
/
mice containing Kupffer cells (Fig.
11). Compared with wild-type mice
containing Kupffer cells, I/R-induced liver injury was reduced by
~85% in Kupffer cell-inhibited gp91
/
mice (Fig. 11).
Not surprisingly, this treatment protocol did not reduce further the
serum levels of TNF-
compared with gp91
/
mice with
intact Kupffer cells (data not shown).
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DISCUSSION |
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I/R-induced liver injury is a consequence of different surgical
manipulations, including transplantation and resectional surgery (7). The duration of ischemia varies considerably
in each of these surgical procedures and pathophysiological situations,
suggesting that the mechanism(s) responsible for postischemic
liver injury may be quite different (7, 15). Because there
has been little attempt to systematically evaluate the mechanisms of
postischemic liver damage following different periods of
ischemia, we wished to define the relationship among Kupffer
cells, O in the pathophysiology of I/R-induced
hepatocellular injury differ depending on the duration of ischemia.
One of the most consistent findings in our present study was the rather
remarkable protective effects provided by the three different SODs with
varying circulating half-lives in vivo (Fig. 5). Although our data
agree well with those of other investigators (18,
47-49) who used native and modified forms of the cytosolic isoform of SOD (e.g., CuZnSOD), the present study demonstrates more
dramatic protective effects in that pcMnSOD decreases liver injury
(60-80%) following both 45 and 90 min of ischemia.
Addition of a 26-amino acid polycationic tail to human MnSOD makes this enzyme capable of binding to the negatively charged heparan sulfate residues found on the surface of sinusoidal and microvascular endothelial cells, thereby extending its half-life in vivo from 6 min
for native SOD to 30 h for pcMnSOD (38). Previous
studies required the use of large quantities of enzymatic scavengers to achieve even more modest protection (18), whereas we
attained a much greater degree of protection by using ~10-fold less
SOD as in the other studies (47, 49). The reasons for
these differences are not readily apparent but are most likely due to
the localization of pcMnSOD to the sinusoidal endothelial cells
(SECs) or the microvascular endothelium. Previous studies have
utilized genetically or chemically modified forms of CuZnSOD and
catalase to target these antioxidants to specific cells within the
liver, where they are endocytosed and maintained within the cell
(18). The polycationic MnSOD used in the present study has
been engineered to possess binding characteristics similar to native
extracellular CuZnSOD, which readily binds to the heparin
sulfate-binding regions on the surface of endothelial cells
(38). Localization to the surface of SECs, for example,
would increase the effective concentration of the antioxidant in an
environment (e.g., extracellular space) deficient in antioxidant
enzymes. Indeed, our data suggest that extracellular O
Another interesting aspect of the data obtained in the present study
was that both short-lived SODs (e.g., native MnSOD and AEOL-10150)
afforded protection equal to that of long-lived pcMnSOD following 45 min of ischemia and 6 h of reperfusion (Fig. 5). These
data agree with other investigators (5, 31) who
demonstrated protective effects using similar low-molecular-weight SOD
mimetics in models of intestinal or brain ischemia.
Since the circulating half-lives of AEOL-10150 and MnSOD are ~22 and
6 min, respectively, our data suggest that O, our data as well as those of other investigators
(13, 22, 23, 30) suggest that NO production is protective
and not a component of a much more damaging species and that its
removal leads to substantial increases in postischemic liver
injury. Together, our data suggest that the early generation of
O
Data obtained in the current study also suggest interesting
relationships among O
expression, and hepatocellular injury following different periods of
ischemia. A number of previous studies have implicated TNF-
in the generation of postischemic liver injury, especially that
associated with the neutrophil-dependent subacute phase
(4). Only recently has there been data to suggest that
this cytokine is an important component of the neutrophil-independent
liver injury (40). Using a monoclonal antibody directed
against mouse TNF-
, we demonstrated that this cytokine is an
important mediator of tissue injury following 90 but not 45 min of
ischemia, despite the fact that both periods of
ischemia produce similar increases in serum levels of TNF-
(Figs. 3 and 4). Our observation that short periods of ischemia
(45 min) involve an O
-independent mechanism of liver injury is further supported by
data demonstrating that, whereas short-lived SODs (e.g., MnSOD and
AEOL-10150) attenuate reperfusion injury, they do not significantly reduce serum levels of TNF-
following 45 min of ischemia
(Figs. 5 and 6). However, when the duration of ischemia is
increased, we observed a more direct relationship among
O
expression, and liver injury.
For example, we observed that ~40-50% of the total
postischemic liver injury is dependent on O
expression following 90 min of ischemia (Figs. 7 and 8). These data are consistent with
the hypothesis that NADPH oxidase-derived O
, which directly or indirectly mediates the
I/R-induced liver damage. Indeed, pretreatment of gp91
/
mice with TNF-
monoclonal antibody offered no additional protection compared with gp91
/
mice treated with IgG control
antibody (data not shown). If one assumes that the mechanisms
responsible for liver injury following 90 min of ischemia
represents the sum of both NADPH oxidase-dependent and -independent
sources of O
Since we show that postischemic liver injury occurs in the
absence of a significant neutrophil infiltration, the most likely cellular sources of NADPH oxidase are the Kupffer cells and possibly the sinusoidal and/or microvascular endothelial cells (9). Indeed, we demonstrated that Kupffer cells may account for as much as
60-80% of the reperfusion injury, depending on the duration of
ischemia (Fig. 9). In this study, we did choose to use
GdCl3 to inactivate Kupffer cells. It should be noted that
this maneuver may not completely eliminate Kupffer cells from the liver
but may simply serve to inactivate them. Thus we may actually be
underestimating the role of Kupffer cells within the
postischemic liver in our model. On the basis of work by other
investigators, one would predict that Kupffer cell-associated NADPH
oxidase plays a major role in the pathophysiology of liver injury
induced by longer periods of ischemia (2, 18, 36).
The mechanisms by which longer periods activate the NADPH complex are
incompletely understood at the present time. Our data would suggest
that factors released during extended ischemic periods are
capable of activating this complex, whether it be located within the
Kupffer cells and/or endothelial cells. One possible mechanism for this
time-dependent activation may be related to portal congestion-induced
intestinal ischemia. It is known that serum levels of bacterial
products increase following intestinal hypoperfusion, either through
hemorrhagic shock or direct interruption of arterial flow
(45). In our studies, we took care to provide adequate
portal flow through the nonischemic lobes. However, this
reduced volume (~30%) of liver could lead to at least partial portal
congestion. Extended periods of impaired flow through the intestine may
then lead to altered intestinal barrier function and subsequent
bacterial translocation, activation of Kupffer cell and/or endothelial
cell-associated NADPH oxidase, and production of O
In summary, this study has identified significant differences in the
mechanisms of postischemic liver injury following short vs.
long periods of ischemia. Although hepatocellular injury
induced by short periods of ischemia appears to require Kupffer
cells and the NADPH oxidase-independent production of
O. Data generated from
this study may provide for a more rational approach to the design of
new drug therapies to treat postischemic liver injury.
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ACKNOWLEDGEMENTS |
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We would like to thank Dr. James Crapo for his helpful discussions and donation of the AEOL-10150 compound.
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FOOTNOTES |
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This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK-43785 and DK-47663) and the Arthritis Center of Excellence at LSU Health Sciences Center.
Address for reprint requests and other correspondence: M. B. Grisham, Dept. of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130 (E-mail: mgrish{at}lsuhsc.edu).
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. Section 1734 solely to indicate this fact.
First published November 20, 2002;10.1152/ajpgi.00400.2002
Received 18 September 2002; accepted in final form 18 November 2002.
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