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Infection and Immunity, March 1999, p. 1018-1024, Vol. 67, No. 3
Department of Microbiology and Immunology and
Division of Bacterial Toxin, Research Center for Infectious Disease,
Aichi Medical University, Nagakute, Aichi 480-1195, Japan
Received 29 July 1998/Returned for modification 15 October
1998/Accepted 4 December 1998
The role of nitric oxide (NO) in lipopolysaccharide (LPS)-induced
hepatic injury was studied in D-galactosamine
(D-GalN)-sensitized mice. The inducible isoform of NO
synthase (iNOS) was immunohistochemically detected on hepatocytes
around blood vessels in livers of mice injected with D-GalN
and LPS not on hepatocytes in mice injected with D-GalN or
LPS alone, although mRNA for iNOS was found in those mice.
Nitrotyrosine (NT) was also found in livers of mice injected with
D-GalN and LPS. The localization of NT was consistent with
that of iNOS, and the time courses of NT and iNOS expression were
almost the same. Expression of iNOS and NT was detected exclusively in
the hepatic lesions of mice injected with D-GalN and LPS.
Anti-tumor necrosis factor alpha neutralizing antibody inhibited iNOS
and NT expression and hepatic injury. The results suggested that NO from iNOS may play a role in LPS-induced hepatic injury on
D-GalN-sensitized mice as an experimental endotoxic shock model.
Nitric oxide (NO) exhibits a wide
range of important functions in vivo, acting as a relaxing factor
mediating vasodilation, a neuronal messenger molecule, and a major
regulatory molecule and principal cytotoxic mediator of the immune
system (3, 7, 18). The signal (messenger) molecule NO is
synthesized by constitutively expressed NO synthase (NOS) for short
periods of time. The killer (cytotoxic) molecule NO is synthesized by
an inducible isoform of NOS (iNOS) that, once expressed, produces NO
for long periods of time (18). It appears paradoxical that
NO can both act as a physiological intercellular messenger and display
cytotoxic activity in vivo (18). Cytotoxicity usually
correlates with NO produced by iNOS (18). Further, NO and
superoxide rapidly react to yield peroxynitrite (1, 3, 27),
a potent oxidant which reacts with proteins, lipid, and DNA (3,
18, 31). Some of the biochemical and toxicological effects of NO
are suggested to occur via peroxynitrite because of the relatively poor
reactivity of NO (29, 32). Peroxynitrite is a highly
reactive species which causes nitration and hydroxylation of tyrosine
and tryptophan as well as DNA injury (3, 27, 31).
Nitrotyrosine (NT) is a convenient in vivo marker of peroxynitrite
(2, 5). The formation of NO, especially peroxynitrite, has
been implicated in the pathophysiology of numerous inflammation
diseases, including sepsis (14, 15).
Bacterial lipopolysaccharide (LPS) is present on the outer membranes of
all gram-negative bacteria and causes the systemic inflammatory
response syndrome and septic shock, which finally develop to multiorgan
failure. Sensitization with D-galactosamine (D-GalN) greatly increases the sensitivity of animals to
LPS and augments the lethal activity of LPS (10, 11).
LPS-induced lethality is characterized by liver failure, accompanied by
severe hepatic injuries. The lethal effect of LPS in
D-GalN-sensitized mice is usually considered an
experimental model for clinical endotoxic shock or septic shock
(11). Previously it was reported that LPS-induced hepatic
injury is caused by hepatocyte apoptosis, mediated mainly by tumor
necrosis factor alpha (TNF- Mice.
Female BALB/c mice were purchased from Japan SLC
(Hamamatsu, Japan) and used at approximately 7 weeks of age.
Reagents.
Rabbit polyclonal immunoglobulin G (IgG)
antibodies to iNOS and NT were obtained from Upstate Biotechnology,
Inc., Lake Placid, N.Y., and Affinity Bioreagents Inc., Neshanic
Station, N.J., respectively. As a second antibody, horseradish
peroxidase-conjugated affinity-purified goat anti-rabbit IgG was
purchased from BioSource International (Camarillo, Calif.). Rabbit
polyclonal antibody neutralizing murine TNF- LPS and administration.
The LPS preparation extracted by the
phenol-water method from Escherichia coli O111:B4 was
obtained from Difco Laboratories, Detroit, Mich. Mice were injected
intraperitoneally (i.p.) with D-GalN (20 mg) and LPS (1 µg). Three to four mice per experimental group were sacrificed 6 h after injection unless otherwise stated, and the livers were removed.
Treatment with D-GalN and LPS led to greater than 80%
lethality in mice.
Immunohistochemical staining.
The livers from mice injected
i.p. with D-GalN and LPS were fixed in 4% formaldehyde.
Paraffin sections of the livers were deparaffinized, and the endogenous
peroxidase activity was blocked with methanol containing 0.3% hydrogen
peroxide for 15 min at room temperature. The sections were washed in
0.01 M phosphate-buffered saline, pH 7.2 (PBS), containing 10% normal
horse serum and incubated overnight at 4°C with anti-iNOS antibody
(1:500) or anti-NT antibody (1:300). Horseradish-conjugated goat
anti-rabbit Ig antibody was used at 1:200 after washing. Immune
complexes were detected with a solution of 3,3-diaminobenzidine (0.2 mg/ml) and hydrogen peroxide in 0.05 M Tris-HCl buffer. Sections were
counterstained with methyl green. In negative control sections, rabbit
antiserum against ovalbumin (1:500) was used as an irrelevant antibody.
Measurement of mRNA levels for iNOS by RT-PCR.
Oligonucleotide primers used for reverse transcription (RT)-PCR,
designed based on the DNA sequence, were iNOS-1
(5'-CTGCAGGTCTTTGACGCTCG-3'), iNOS-2
(5'-GTGGAACACAGGGGTGATGC-3'), GAPDH-1
(5'-AGATCCACAACGGATACATT-3'), and GAPDH-2
(5'-TCCCTCAAGATTGTCAGCAA-3'). Total RNA was extracted from
livers (100 µg) by a modified guanidinium isothiocyanate method using
the RNA extraction reagent Isogen (Nippon Gene, Toyama, Japan) as
instructed by the manufacturer. Separate aliquots of total RNA were
reverse transcribed into cDNA and subjected to RT-PCR using the Titan
One Tube RT-PCR system, PCR nucleotide mix, and RNase inhibitor
(Boehringer, Mannheim, Germany). The reaction mixture was amplified
with a thermal cycler for 30 min as recommended by the manufacturer.
After an initial denaturation step at 94°C for 2 min, each cycle
consisted of incubations at 94°C for 30 s, 59°C for 30 s,
and 68°C for 2 min. Products were analyzed on a 3% agarose 21 gel
(Nippon Gene) and visualized under UV light by staining with ethidium
bromide. The iNOS primers used for the RT-PCR included the murine
macrophage sequence for iNOS from positions 607 to 1413 (13,
22). The RT-PCRs resulted in the amplification of a single
product of the predicted size for the iNOS (807 bp) (13). To
ensure that equal amounts of reverse-transcribed RNA were applied to
the RT-PCR, the parallel expression of glyceraldehyde-3-phosphate
dehydrogenase (GAPDH) mRNA was tested at 30 min.
Detection of mRNA levels for iNOS in livers of mice injected with
D-GalN and LPS.
Induction of the mRNA for iNOS in
livers of mice injected with D-GalN, LPS, or the mixture of
D-GalN and LPS was analyzed by RT-PCR. Mice were injected
i.p. with D-GalN, LPS, or a mixture of D-GalN
and LPS, and livers were removed 3 h after the injection. The PCR
products for iNOS were detected in livers of mice injected with of
D-GalN, LPS, or the mixture of D-GalN and LPS.
RT-PCR yielded amplified products with a length of about 807 bp (Fig. 1), consistent with the base pair size
expected from the nucleotide sequence of the iNOS in mouse macrophages
(13, 22). However, mRNA for iNOS was undetectable in
saline-injected control mice. In addition, the treatments did not alter
levels of mRNA for the housekeeping gene GAPDH in livers.
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Role of Nitric Oxide in Lipopolysaccharide-Induced Hepatic
Injury in D-Galactosamine-Sensitized Mice as an
Experimental Endotoxic Shock Model
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
) (20, 24). However, there are
no reports on the participation of NO in the LPS-induced hepatic injury
of D-GalN-sensitized mice. In the present study, we
examined whether and how NO participates in LPS-induced hepatic injury
in D-GalN-sensitized mice as an experimental endotoxic
shock model.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
, hamster antibody
neutralizing gamma interferon or interleukin-1, and murine recombinant
TNF- were purchased from Genzyme (Cambridge, Mass.) and used as
recommended by the manufacturer.
RESULTS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
View larger version (73K):
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FIG. 1.
Detection of iNOS mRNA in livers of mice injected with
D-GalN and LPS. iNOS mRNA products of 807 bp were obtained
after amplification using total RNA from mice injected with PBS (lanes
2 and 3), D-GalN (lanes 4 and 5), LPS (lanes 6 and 7), or
D-GalN and LPS (lanes 8 and 9). Lane 1, DNA size marker;
lanes 2 to 9, mRNA products of iNOS (lanes 3, 5, 7, and 9) and the
housekeeping gene GAPDH (lanes 2, 4, 6, and 8). The arrow
indicates the size of the expected amplification product of the mRNA
for iNOS.
Detection and localization of iNOS in livers of mice injected with D-GalN and LPS. In the experiments described above, the administration of D-GalN, LPS, or the mixture of D-GalN and LPS resulted in induction of the mRNA for iNOS. The expression and localization of iNOS in livers of the mice were studied immunohistochemically with anti-iNOS antibody (Fig. 2). Mice were injected i.p. with D-GalN, LPS, or the mixture of D-GalN and LPS, and livers were removed 6 h after injection. Positive staining was detected exclusively in livers of mice injected with the mixture of D-GalN and LPS. No significant staining was detected in livers of mice injected with D-GalN or LPS alone, although the mRNA for iNOS was found by RT-PCR. The expression of iNOS was detected mainly around blood vessels in livers of mice injected with D-GalN and LPS. Hepatocytes and some vascular endothelial cells were stained positively.
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Detection and localization of NT in livers of mice injected with D-GalN and LPS. Since NO probably exerts its toxic effects via peroxynitrite and peroxynitrite causes the nitration of tyrosine (2, 5), we performed immunohistochemical staining to detect NT as a convenient in vivo marker of peroxynitrite. Mice were injected i.p. with D-GalN, LPS, or the mixture of D-GalN and LPS, and livers were removed 6 h after injection. The result is shown in Fig. 3. NT was detected only in livers from mice injected with the mixture of D-GalN and LPS. Positively stained cells were hepatocytes and vascular endothelial cells around blood vessels of those mice. NT was not found in livers of mice injected with D-GalN or LPS alone. The localization of NT corresponded to that of iNOS.
|
Time course of iNOS and NT expression in livers of mice injected with D-GalN and LPS. The time course of iNOS and NT expression was monitored in livers of mice injected with D-GalN and LPS. The result is shown in Fig. 4. Weak expression of iNOS around blood vessels in the livers was found 3 h after the injection. Staining of iNOS was much more apparent 6 h after injection, and positive staining was found diffusely around blood vessels. Similarly, expression of NT was detected 3 h and increased up to 6 h after injection. NT was also detected around blood vessels. The staining pattern of NT was almost the same as that of iNOS.
|
Histology of hepatic injury in mice injected with D-GalN and LPS. LPS-induced hepatic injury of D-GalN-sensitized mice was histologically inspected in livers of mice injected with D-GalN and LPS. Mice were injected with D-GalN, LPS, and the mixture of D-GalN and LPS, and livers were removed from live mice 12 h after the injection. Hematoxylin and eosin-stained liver sections are shown in Fig. 5. Histological changes were found only in livers of mice injected with D-GalN and LPS, not in livers of mice injected with D-GalN or LPS alone. Vascular walls in livers of those mice became thin and were in part destroyed. Vascular endothelial cells exhibited damage, accompanied by hemorrhage into the parenchymal region. In particular, hepatocytes around blood vessels were massively damaged (Fig. 5a); some of the nuclei were fragmented and condensed (Fig. 5b). Hepatic lesions in mice injected with D-GalN and LPS corresponded to the localization of iNOS and NT.
|
Role of TNF- in the induction of iNOS and NT in livers of mice
injected with D-GalN and LPS.
A major feature of
LPS-induced hepatic injury of D-GalN-sensitized mice is
increased sensitivity to TNF-mediated effects (19, 24).
Previously we reported that hepatocyte injury in mice injected with
D-GalN and LPS was inhibited by anti-TNF- antibody and
that recombinant TNF and D-GalN produced similar hepatic
injuries (24). Based on those findings, we studied the
participation of TNF- in induction of iNOS and NT (Fig.
6). Mice were injected with anti-TNF-
antibody (50 µg) together with D-GalN and LPS.
Anti-TNF- antibody significantly blocked the induction of iNOS and
NT, suggesting the participation of TNF-. Next, mice were injected
with TNF- (50 ng) and D-GalN to confirm the involvement
of TNF-. The administration of recombinant TNF- and
D-GalN caused the expression of iNOS and NT around blood
vessels, implicating TNF- in LPS-induced expression of iNOS and NT.
In addition, anti-gamma interferon or anti-interleukin-1 antibody (50 µg) did not block the expression of iNOS and NT (data not shown).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
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In this study, we demonstrated that the administration of
D-GalN and LPS to mice induced the expression of iNOS and
NT in livers. iNOS and NT expression was detected at the sites of
LPS-induced hepatic injury in D-GalN-sensitized mice.
Further, iNOS and NT expression preceded hepatic injury. Neutralization
of TNF- with the antibody inhibited iNOS and NT expression as well
as LPS-induced hepatic injury, suggesting that the expression of iNOS
and NT was closely associated with hepatic injury in livers of mice
injected with D-GalN and LPS. On the other hand, iNOS and
NT expression was not detected in mice injected with LPS or
D-GalN alone, although RT-PCR analysis indicated that mRNA
for iNOS may have been marginally transcribed in those cases.
Considering that the killer molecule NO is synthesized by iNOS
(18), it was reasonable that no significant hepatic lesions
were produced in livers of mice injected with LPS or D-GalN
alone. Killer NO molecules produced by iNOS may be important in the
development of LPS-induced hepatic injury in
D-GalN-sensitized mice. To our knowledge, the induction of iNOS and production of NO and NT in LPS-induced hepatic injury of
D-GalN-sensitized mice have not been investigated, although an animal model of sepsis caused by gram-positive organisms has recently been developed (30).
A number of studies have examined the relationship between NO production and tissue injury (23, 26, 29, 34-36). The toxicological effect of NO seems to occur via peroxynitrite because of the relatively poor reactivity of NO and the formation of NT at sites of enhanced NO synthesis (29, 32). Peroxynitrite, a potent oxidant formed from NO and superoxide, causes the nitration of tyrosine (3). Therefore, NT is a convenient in vivo marker of peroxynitrite (2, 5). Since NT was detected at the sites of LPS-induced hepatic injury, peroxynitrite appeared to participate in hepatic injury in mice injected with D-GalN and LPS. NO and superoxide may be produced by vascular endothelial cells and circulating leukocytes, and the reaction forming peroxynitrite may occur around blood vessels, possibly in association with the development of hepatic injury around blood vessels.
Recent studies demonstrate that NO and peroxynitrite cause either
necrosis or apoptosis in a variety of cell types (4, 9, 21,
28). It appears that sustained exposure to low levels of NO or
peroxynitrite causes apoptosis, whereas sudden exposure to high
concentrations of peroxynitrite or NO results in cell necrosis
(31). Of particular interest was whether hepatic injury in
livers of mice injected with D-GalN and LPS was due to
apoptosis or necrosis. Previously we reported the DNA ladder pattern in agarose gel electrophoresis and fragmented nuclei in livers of mice
injected with D-GalN and LPS, suggesting hepatocyte
apoptosis (24). The present study also demonstrated
fragmented and condensed nuclei of hepatocytes around blood vessels. It
was suggested that LPS-induced hepatic injury in the system may be due
to NO- and peroxynitrite-mediated apoptosis. On the other hand,
antiapoptotic effects of NO were reported (7, 8, 18). In
vivo antiapoptotic effects of NO are probably indirect effects of NO as
a consequence of its improvement of blood circulation in vivo in tissue
injury (18). In the present study, it was unlikely that NO
production by iNOS exerted an antiapoptotic effect because anti-TNF-
antibody blocked both iNOS and NT expression and hepatic injury.
Previously we reported that TNF is a key molecule in LPS-induced
hepatic injury of D-GalN-sensitized mice (24).
In fact, simultaneous injection of anti-TNF- antibody with
D-GalN and LPS prevented LPS-induced hepatic injury of
D-GalN-sensitized mice and lethality (24). In
the present study, anti-TNF- antibody blocked the expression of iNOS
and NT, and the injection of recombinant TNF- into
D-GalN-sensitized mice significantly induced the expression of iNOS and NT. TNF- was suggested to play a critical role in LPS-induced NO production, although it is known that interleukin-1 and
platelet-activating factor can induce iNOS (12, 33).
Interleukin-1- or gamma interferon-specific antibody did not block
LPS-induced hepatic injury, which suggested that (i) TNF- may be
primarily responsible for hepatic injury and (ii) TNF--induced NO
production may participate in the development of hepatic injury. It was
recently reported that the lethal dose of LPS in
D-GalN-sensitized mice correlated with in vitro TNF- and
NO production in a macrophage cell line treated with the same LPS
(6), which also supported our conclusions derived from the
present study.
Recently we demonstrated the expression of inducible heat shock protein 70 (HSP70) in livers of mice injected with D-GalN and LPS (25). The localization of inducible HSP70 was consistent with that of iNOS expression in this study. It was reported that NO potently stimulates the induction of the heat shock proteins HSP70 and HSP32 (16, 17). HSP induction confers resistance to subsequent apoptotic stimuli (7). NO makes some hepatocytes undergo apoptosis via peroxynitrite-mediated DNA damage, whereas it makes other hepatocytes survive through the production of HSPs. Possibly some hepatocytes, which did not exhibit sufficient autoprotective stress response to LPS stimuli, underwent apoptotic cell death. It is of interest to investigate how LPS-induced NO production may regulate cell death and stress responses.
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ACKNOWLEDGMENTS |
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This work was supported by a grant from the Ministry of Education, Science and Culture of Japan.
We thank K. Takahashi for technical assistance.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Microbiology and Immunology, Aichi Medical University, Nagakute, Aichi 480-1195, Japan. Phone: 81-561-62-3311, ext. 2269. Fax: 81-561-63-9187. E-mail: yokochi{at}amugw.aichi-med-u.ac.jp.
Editor: R. N. Moore
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Abstract
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Materials and Methods
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Discussion
References
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Infection and Immunity, March 1999, p. 1018-1024, Vol. 67, No. 3
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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