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* Department of Pathology, Department of Internal Medicine,
§ Division of Pulmonary and Critical Care, and
Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan 48109-0602, USA; and
Department of Medicine, University of Edinburgh, Edinburgh, U.K.
1Correspondence: Department of Pathology, University of Michigan Medical School, 1301 E Catherine, Ann Arbor MI 48109-0602, USA. E-mail: hogaboam{at}path.med.umich.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Key Words: acetaminophen • acute liver injury • hepatic regeneration
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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acetaminophen overdose often manifest many hours after
major hepatic injury has occurred. When administered within 8 h
(2)
, N-acetyl-cysteine
(NAC),2
a precursor of glutathione that is the standard medical treatment for
acetaminophen overdose cases, effectively inhibits liver injury and
prevents fulminant hepatic failure. However, because the onset of
symptoms of acetaminophen overdose may be delayed or misinterpreted,
the therapeutic window for NAC treatment of acetaminophen toxicity is
frequently missed (3)
. Despite advances in supportive
care, acute hepatic failure attributed to acetaminophen ingestion
approaches 50% in the United Kingdom (4)
. A liver
transplant will ensure patient survival in these cases
(5)
, but the majority of patients affected by
acetaminophen overdose do not fulfill all the necessary criteria for
liver transplantation because they lack co-existent renal failure or
severe acidosis (6)
. At present, considerable experimental
attention is directed at elucidating factors that promote rapid and
maximal liver regeneration after exposure of the liver to toxic or
mechanical insults (7)
. Cytokines, particularly tumor
necrosis factor 
(TNF-) (8)
and interleukin 6 (IL-6)
(9)
, are among newly described factors that possess unique
liver regenerative qualities. Additional studies have shown that
elevations in TNF- and IL-6 in the damaged liver directly promote
the de novo generation of ELR-containing CXC chemokines such
as MIP-2 and ENA-78 (10
, 11)
. These chemokines have been
shown to contribute to the inflammatory process that follows acute
hepatic injury (12
, 13)
, but their role during the liver
regenerative process remains largely unexplored. ELR-CXC chemokines are
distinct from other CXC chemotactic cytokines because these mediators
contain three amino acid residues, Glu-Leu-Arg (i.e., ELR), which are
immediately next to the CXC motif, and the majority of ELR-CXC
chemokines bind to CXC chemokine receptor 2 (CXCR2) (14)
.
Since ELR-CXC chemokines also exert mitogenic effects on a number of
structural-type cells (reviewed in ref 15
), we compared
the therapeutic efficacy of NAC and hepatocyte growth factor (HGF)
(7)
with that of ELR-CXC chemokines in fasted mice
challenged with acetaminophen. Superior therapeutic effects of MIP-2
[an interleukin 8-related chemokine present in rodents
(16)
], human IL-8, and ENA-78 were observed when any one
of these ELR-CXC chemokines was intravenously (i.v.) infused into mice
10 h after acetaminophen challenge. Conversely, delayed NAC, IP-10
(a non-ELR-CXC chemokine), or HGF treatment did not attenuate liver
injury in acetaminophen-challenged mice. It was also apparent from
in vitro experiments that ELR-CXC chemokines had CXC
receptor 2 (CXCR2) -dependent mitogenic effects on cultured
hepatocytes. Taken together, these data suggest that ELR-CXC chemokines
can reverse acetaminophen-induced liver injury and exert prominent
therapeutic effects when NAC treatment is ineffective against
acetaminophen-induced hepatotoxicity.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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.
Experimental protocols
In the first set of experiments, groups of fasted CD1 mice were
pretreated with preimmune rabbit serum or polyclonal rabbit anti-mouse
antibody directed against the ELR-CXC chemokine receptor CXCR2; these
mice were killed at 6, 48, and 144 h after acetaminophen challenge
for histological examination of liver tissue. All polyclonal rabbit
antibodies were generated and screened to ensure specificity prior to
use as described previously in detail (18)
; the biological
half-life of these immunoneutralizing antibodies was ~36 h
(10)
. The anti-CXCR2 antibody inhibited KC-induced
neutrophil influx into the peritoneum of mice and the MIP-2- and
KC-induced angiogenesis in the rat cornea (R. M. Strieter,
personal communication). Additional groups of mice (n=5–8
mice/group) were pretreated with 0.5 ml of preimmune rabbit serum or
the same volume of polyclonal rabbit anti-mouse MIP-2 antibody 2 h
prior to acetaminophen challenge. Mice were killed at 144 h after
acetaminophen challenge and livers were prepared for histological
examination.
In the next set of experiments, mice were fasted for 12 h and received one dose of NAC, murine MIP-2, and the human proteins ENA-78, IL-8, HGF, or IP-10 either immediately or 10 h after acetaminophen challenge. Recombinant chemokines and HGF were obtained from R&D Systems (Minneapolis, Minn.) or Pepro Tech (Rockyhill, N.J.); NAC was obtained from Sigma. Mice were injected i.v. with 100 µg of NAC or 2 µg of recombinant protein dissolved in 0.5 ml of normal saline. All mice were subsequently killed 48 h after acetaminophen challenge, and serum and liver samples were removed.
In the final set of experiments, mice were fasted for 24 h and received MIP-2 (2 µg) or NAC (100 µg) via an i.v. injection either immediately or 10 h after acetaminophen challenge; liver and serum samples were removed from surviving mice 48 h after acetaminophen challenge. Liver and serum samples from the experimental groups and from mice challenged with an i.p. injection of PBS and treated i.v. with normal saline were processed as described below.
Chemokine ELISAs
Immunoreactive levels of CC and CXC chemokines were measured in
liver homogenates using a modified double-ligand enzyme-linked
immunoassay (ELISA) procedure as described in detail elsewhere
(18)
. Before each ELISA, snap-frozen liver samples were
thawed on ice, weighed, and homogenized in solution containing 2 mg of
protease inhibitor (Complete; Boehringer Mannheim, Indianapolis, Ind.)
per milliliter of normal saline. Previous studies in this laboratory
have shown that Complete does not interfere with any of the chemokine
ELISAs (18)
. Cell-free supernatants from the liver
homogenates were loaded in duplicate onto 96-well microtiter plates
coated with the appropriate capture antibody and blocked with 2%
bovine serum albumin in PBS. Each ELISA consistently detected
concentrations of chemokines below 10 pg/ml, and the specificity of the
polyclonal detection and capture antibodies was confirmed prior to its
use in an ELISA. Chemokines levels in liver homogenates were normalized
to the weight of the liver sample assayed.
Serum aspartate aminotransferase
Acute hepatocellular injury results in elevated levels of
aspartate aminotransferase (AST). Serum levels of AST were determined
48 h after mice were challenged with acetaminophen by Clinical
Pathology at the University of Michigan Medical School (Ann Arbor,
Mich.) using standardized techniques.
Histology
For histological assessment of hepatic injury, liver tissues
were fixed in 4% paraformaldehyde for 24 h prior to routine
histological processing. A pathologist assessed hematoxylin- and
eosin-stained slides from acetaminophen-challenged mice in a blinded
manner. Separate scoring systems were devised to indicate the area of
liver necrosis and hemorrhage and the extent of hepatic inflammation.
Detailed histological grading of hepatic injury, including area of
liver necrosis and hemorrhage, was determined at 48 h after
acetaminophen challenge. Hepatic inflammation was graded as absent,
slight, moderate, or prominent.
Cultured hepatocyte proliferation
The effects of chemokines, NAC, and HGF on hepatocyte
proliferation after a 24 h acetaminophen challenge were examined
using normal murine liver cells obtained from American Type Culture
Collection (ATCC CRL-1638; NmuLi). Hepatocytes were plated at a density
of 1.0 x 105 cells/well in 6-well tissue
culture plates and deprived of fetal bovine serum supplementation for
36 h prior to an experiment. Fasted hepatocytes were subsequently
exposed to 2.5 mg/ml of acetaminophen and left untreated or were
treated with NAC, MIP-2, ENA-78, IL-8, IP-10, or HGF. NAC at 1 mM or
individual cytokines at 1 ng/ml were added either immediately or
10 h after the addition of acetaminophen. In additional in
vitro experiments, normal serum or anti-CXCR2 antibody was also
included in cultures of treated or untreated hepatocytes exposed to PBS
or acetaminophen. [3 H]thymidine (10 µCi) was
added to each well for the final 4 h of culture; 24 h after
the addition of acetaminophen, suspensions of hepatocytes were prepared
via cell lysis with 0.5% (v/v) Triton-X100.
[3H]thymidine incorporation was assessed by
liquid scintillation counting on a Beckman counter (Beckman
Instruments, Fullerton, Calif.).
Statistical analysis
Results are expressed as means ± standard error of the
mean (SE) of 5–10 mice per group, and analysis of variance
was used to detect significant differences between means. All
statistical calculations were performed using GraphPad Prism 2.0
computer software (San Diego, Calif.); P 
0.05 was
considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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, 19)
. Thus, the role of
endogenous CXCR2 in the hepatotoxic effects of acetaminophen was
examined in fasted mice that received either neutralizing rabbit
anti-mouse CXCR2 antibody or preimmune rabbit serum 2 h prior to
acetaminophen challenge. As shown in Fig. 1
, anti-CXCR2 antibody pretreatment markedly enhanced the degree of liver
hemorrhage and necrosis at 6 h (Fig. 1B
) and 48 h
(Fig. 1D
) after acetaminophen challenge compared to
acetaminophen-induced injury at 6 h (Fig. 1A
) and
48 h (Fig. 1C
) in preimmune serum-treated mice.
Although mice that received anti-CXCR2 antiserum alone did not show
liver injury at any time point, marked liver necrosis was still
apparent 6 days after acetaminophen challenge in mice that received
anti-CXCR2 antibody (not shown). This was in marked contrast to the
restored liver histology at this time in mice that received preimmune
serum prior to acetaminophen challenge (not shown).
|
Endogenous hepatic levels of murine monocyte chemoattractant
protein-1 (MCP-1), macrophage inflammatory protein-1 (MIP-1),
MIP-2, and KC were determined by ELISA (Table 1
). KC is a murine ELR-CXC chemokine with neutrophil chemotactic
properties (12)
that binds CXCR2 with ~10-fold less
affinity than MIP-2 (19)
The murine CC chemokines MCP-1
and MIP-1 were unchanged in liver homogenates from mice challenged
48 h earlier with 400 mg/kg of acetaminophen. In contrast,
significant elevations in the murine ELR-CXC chemokines MIP-2 and KC
were present in the same liver homogenates.
|
Elucidation of the role of increased MIP-2 levels in the liver was
explored through the use of a polyclonal rabbit antibody directed
against murine MIP-2 or preimmune rabbit serum to mice 2 h prior
to acetaminophen challenge. In mice that did not receive acetaminophen,
the presence of anti-MIP-2 antiserum or normal rabbit serum did not
appear to exert any discernible injurious effect on the liver (not
shown). Histological examination of liver samples on day 6
post-acetaminophen showed that endogenous MIP-2 was critical for normal
liver regeneration in the mouse after acetaminophen challenge
(Fig. 2
). In contrast to mice that received preimmune serum (Fig. 2A
), severe disruption of the hepatic architecture around
central veins was readily apparent in mice that received anti-MIP-2
prior to acetaminophen challenge 6 days previously (Fig. 2B
). Areas of necrosis encompassing > 50% of the
total liver area were apparent in mice pretreated with anti-MIP-2
antibody (see inset to Fig. 2B
).
|
ELR-CXC chemokine vs. NAC therapy during acetaminophen challenge
The therapeutic effects of ELR-CXC chemokines were compared with
those of NAC and HGF therapy during experimental acetaminophen
hepatotoxicity. In untreated CD1 mice, the mean serum AST level was
increased ~20–fold above the baseline value of 99 ± 34 IU/l at
48 h after acetaminophen challenge (Fig. 3
A, B). Among the treatments used immediately after
acetaminophen challenge, NAC treatment reduced AST levels by ~90%
(Fig. 3A
). In addition, all three ELR-CXC chemokines (one
mouse and two human) significantly reduced serum AST levels by ~50%,
but IP-10 (a non-ELR CXC chemokine) and HGF did not lower serum AST
levels in acetaminophen-challenged mice. When treatment was delayed
10 h after acetaminophen challenge, MIP-2, ENA-78, and IL-8, but
neither IP-10 nor NAC, significantly reduced serum AST levels (Fig. 3B
).
|
The hepatic injury observed at 10 h (not shown) and 48 h (representative liver histology shown in Fig. 4
) after acetaminophen challenge was characterized by intense necrosis
and hemorrhage localized around central veins in the liver. In
untreated mice, greater than 50% of the total liver mass was necrotic
and exhibited hemorrhage (Fig. 4A
). Marked attenuation of
liver injury was observed in mice that received 2 µg of MIP-2 (Fig. 4B
), ENA-78 (Fig. 4C
), or IL-8 (Fig. 4D
), but not IP-10 (Fig. 4E
), HGF (Fig. 4F
), or 100 µg of NAC (Fig. 4G
), when these
treatments were delayed until 10 h after acetaminophen challenge.
The beneficial effects of delayed MIP-2, ENA-78, and IL-8 therapy were
most marked around hepatic central veins, where healthy hepatocytes
were readily apparent (Fig. 4B-D
), and the histological
appearance of liver sections in these treatment groups was similar to
that observed in normal mice (Fig. 4H
). In addition,
necrotic injury in acetaminophen-challenged mice treated with ELR-CXC
chemokines was either absent or comprised less than 10% of the liver
area.
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Delayed MIP-2 therapy protects mice from the lethal effects of
acetaminophen
The lethal effects of a 400 mg/kg dose of acetaminophen were
evident when mice were fasted for a longer period. In these
experiments, only 25% of mice fasted for 24 h prior to
acetaminophen challenge survived until day 2 (Table 2
). NAC treatment of mice immediately after acetaminophen challenge
increased mouse survival to 90%, whereas MIP-2 given at the same time
spared ~50% of mice. When NAC treatment was delayed by 10 h
after acetaminophen challenge, the survival rate in this group of mice
was significantly reduced to 25%. However, 60% of mice that received
a similarly delayed treatment of MIP-2 were protected from the lethal
effects of acetaminophen (Table 2)
.
|
Mice that received NAC immediately after acetaminophen challenge
had significantly lower levels of serum AST levels than mice that
received MIP-2 at this time (Fig. 5
). The converse was observed when the NAC and MIP-2 treatments were
delayed for 10 h after acetaminophen challenge. Accordingly, mice
in the delayed MIP-2 treatment group had significantly lower levels of
serum AST compared to mice that received the delayed NAC treatment.
|
The histological appearance of liver tissue removed from these
groups of mice corroborated the changes in serum AST. As shown in
Fig. 6
, the delivery of NAC to mice immediately after (Fig. 6A
) but
not 10 h post (Fig. 6B
) acetaminophen markedly reduced
liver injury. Although mice that received MIP-2 immediately after
acetaminophen challenge exhibited marked liver injury at the 48 h
time point (Fig. 6C)
, the liver appearance in mice that received the
delayed MIP-2 therapy was markedly improved at this time point (Fig. 6D
). Taken together, these findings suggested that when
given immediately after a lethal dose of acetaminophen, NAC was clearly
superior to MIP-2 treatment. However, delayed MIP-2 therapy was clearly
more beneficial compared with a delayed NAC therapy as evidenced by
reduced mouse mortality, serum AST, and liver injury in the delayed
ELR-CXC chemokine therapy group.
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ELR-CXC chemokines maintain hepatocyte proliferation via CXCR2
The liver-regenerative properties of ELR-CXC chemokines were
also explored in vitro using a normal hepatocyte cell line.
Untreated liver cells were susceptible to the toxic effects of
acetaminophen as evidenced by significantly decreased cell
proliferation (as monitored by [3H]thymidine
incorporation) after exposure to acetaminophen for 24 h
(Fig. 7
A, B). Although NAC did not alter the proliferation of liver
cells exposed to PBS, the addition of NAC to liver cell cultures
immediately after acetaminophen maintained the proliferation of these
cells at levels measured in cell cultures challenged with PBS (Fig. 7A
). Likewise, MIP-2, ENA-78, IL-8 and HGF did not change
the proliferation of liver cells exposed to PBS, but MIP-2 and ENA-78
prevented the drop in liver cell proliferation after exposure to
acetaminophen for 24 h. The non-ELR CXC chemokine IP-10, which
binds CXCR3, lowered the proliferation rate of liver cells exposed to
PBS by 40% compared to control cultures with PBS, but the
proliferative response of liver cells was not further reduced by the
exposure of these cells to acetaminophen. A 10 h delay in the
treatment of the liver cells after acetaminophen challenge
significantly reduced liver cell proliferation in cultures treated with
NAC compared to the respective PBS control cultures (Fig. 7B
). In contrast, all other cultures of liver cells exposed
to acetaminophen that received delayed cytokine or chemokine treatment
showed [3H]thymidine incorporation comparable
to cytokine- or chemokine-treated cultures exposed to PBS.
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The mitogenic properties of ELR-CXC chemokines were also dependent on
their ability to bind to CXCR2, since the presence of a rabbit
anti-mouse CXCR2 antibody significantly reduced the mitogenic effects
of MIP-2, ENA-78, and IL-8 on acetaminophen-challenged liver cells
(Fig. 8
). The presence of anti-CXCR2 antibody also significantly reduced
[3H]thymidine incorporation by NAC-treated
liver cells exposed to acetaminophen for 24 h. However, the
mitogenic effects of IP-10 and HGF on acetaminophen-challenged liver
cells were independent of CXCR2 function. Overall, these in
vitro data suggested that CXC chemokines possess hepatoprotective
effects after acetaminophen challenge due partly to their
CXCR2-dependent mitogenic effects on liver resident cells.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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, potentially leading to liver failure
(20)
. Because the symptoms of acetaminophen overdose
commonly mimic common illnesses, the real diagnosis and the initiation
of NAC therapy may be delayed beyond the time in which NAC effectively
reduces liver injury (21)
. After the therapeutic window of
NAC is passed, liver transplantation is often the only clinical
intervention that will ensure the survival of these patients.
Unfortunately, liver transplant recipients require intensive management
to avoid potential complications due to rejection of the hepatic
transplant (22)
. A novel therapeutic strategy that reduces
the need for liver transplantation after acetaminophen overdose may be
found in the inherent regenerative processes of the liver
(23)
. Despite evidence that the liver possesses a
tremendous capacity to regenerate after hepatic injury, few biological
substances have been identified that, when delivered several hours
after liver injury has occurred, promote a rapid hepatocyte
proliferative response to counteract the profound hepatic necrosis that
follows acetaminophen-induced toxicity.
Centrilobular hepatocytes have the important role of metabolizing
many of the drugs introduced into the liver (24)
. When
exposed to acetaminophen, the hepatocyte uses glutathione to neutralize
the toxic effects of the primary metabolite of acetaminophen,
N-acetyl-p-benzoquinoneimine. The toxic effects of this
metabolite can be reversed with the addition of NAC, but the efficacy
of this compound declines precipitously as hepatocytes succumb to the
toxic effects of N-acetyl-p-benzoquinoneimine. Delayed NAC
treatment for acetaminophen-induced hepatotoxicity fails, in part,
because this drug fails to trigger the restoration of the critical mass
of hepatocytes needed for liver function. This was confirmed in the
present study by the failure of delayed NAC treatment to prevent
acetaminophen-induced liver damage observed in vivo and the
decreased liver cell proliferation observed in vitro after
acetaminophen challenge. Consequently, at the latter stages of
drug-induced hepatotoxicity, the proliferation of the normally
quiescent hepatocyte is paramount to prevent fulminant hepatic failure
(23)
. However, many of the factors that promote the
proliferation of cultured hepatocytes do not necessarily exhibit liver
regenerative effects in vivo (7)
. The in
vitro data presented herein showed that ELR-CXC chemokines, HGF,
and IP-10 effectively maintained hepatocyte proliferation in the
presence of toxic levels of acetaminophen. More important, the
mitogenic effect of these factors was still evident when these
mediators were added to hepatocytes with prior exposure to
acetaminophen for 10 h. However, unlike the ELR-CXC chemokines,
neither the immediate or delayed injection of HGF or IP-10 into
acetaminophen-challenged mice promoted rapid liver restoration after
acetaminophen-induced injury. Thus, these data demonstrate that ELR-CXC
chemokines possess novel hepatic regenerative properties that were
consistently observed during in vivo and in vitro
acetaminophen challenge of hepatic tissue.
CXC chemokines are widely recognized as inflammatory cell recruitment
factors (15)
. Nevertheless, the list of functions
attributable to CXC chemokines has recently expanded and newer
biological effects of these mediators include angiogenesis
(25)
and mitogenesis (16)
. In particular, the
newly described properties of ELR-CXC chemokines are attributed mainly
to the ELR motif (25
, 26)
. ELR-CXC chemokines are specific
for CXCR1 and CXCR2, whereas the non-ELR-CXC chemokines (that lack
angiogenic and mitogenic effects) typically bind to CXCR3 and CXCR4.
Several lines of evidence suggest that ELR-CXC chemokines may by
critical participants in generalized wound healing responses. First,
elevated levels of ELR-CXC chemokines and CXCR2 are invariably found in
damaged tissues, including the liver (27)
and skin
(28)
. Second, ELR-CXC chemokines have previously been
shown to have potent mitogenic effects on several tissue resident
cells, including keratinocytes (29)
, epithelial cells
(16)
, endothelial cells (30)
, and hepatocytes
(11)
. Third, many of the previously mentioned cells
exhibit de novo synthesis of ELR-CXC chemokines after
inflammatory stimuli. For example, hepatocytes (31)
and
hepatic stellate cells (13)
have been shown to generate
ELR-CXC chemokines after exposure to acetaminophen or other
inflammatory stimuli. Liver injury precipitated by hepatectomy is also
associated with dramatic increases in MIP-2 and ENA-78
(10)
, the absence of which after antibody-mediated
immunoneutralization significantly impairs normal liver regeneration
(11)
. The precise cellular mechanism by which ELR-CXC
chemokines facilitate hepatocyte proliferation is being investigated.
Thus, the novel hepatocyte regenerative properties of ELR-CXC
chemokines may represent another viable therapeutic intervention in the
acetaminophen-damaged liver that may obviate or postpone the need for
liver transplantation.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received for publication January 11, 1999. Revised for publication March 30, 1999.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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X. Cao, W. Zhang, T. Wan, L. He, T. Chen, Z. Yuan, S. Ma, Y. Yu, and G. Chen Molecular Cloning and Characterization of a Novel CXC Chemokine Macrophage Inflammatory Protein-2{gamma} Chemoattractant for Human Neutrophils and Dendritic Cells J. Immunol., September 1, 2000; 165(5): 2588 - 2595. [Abstract] [Full Text] [PDF]
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 C. M. Hogaboam, C. L. Bone-Larson, M. L. Steinhauser, A. Matsukawa, J. Gosling, L. Boring, I. F. Charo, K. J. Simpson, N. W. Lukacs, and S. L. Kunkel Exaggerated Hepatic Injury Due to Acetaminophen Challenge in Mice Lacking C-C Chemokine Receptor 2 Am. J. Pathol., April 1, 2000; 156(4): 1245 - 1252. [Abstract] [Full Text]< |
