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Journal of Virology, March 2000, p. 2472-2476, Vol. 74, No. 5
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Therapeutic Effect of Anti-Macrophage Inflammatory
Protein 2 Antibody on Influenza Virus-Induced Pneumonia in
Mice
Shinya
Sakai,1
Hiroshi
Kawamata,1
Naoki
Mantani,1
Toshiaki
Kogure,1
Yutaka
Shimada,1
Katsutoshi
Terasawa,1
Takeshi
Sakai,2
Nobuko
Imanishi,3 and
Hiroshi
Ochiai3,*
Department of Japanese Oriental
Medicine,1 Second Department of
Pathology,2 and Department of Human
Science,3 Faculty of Medicine, Toyama Medical
and Pharmaceutical University, Toyama, Japan
Received 16 August 1999/Accepted 7 December 1999
 |
ABSTRACT |
We investigated the effect of anti-macrophage inflammatory protein
2 immunoglobulin G (aMIP-2 IgG) on the progression of influenza virus-induced pneumonia in mice. When mice were infected with a mouse
lung-adapted strain of influenza A/PR/8/34 virus by intranasal inoculation, neutrophil counts in the bronchoalveolar lavage fluid (BALF) increased in parallel with the kinetics of MIP-2 production, which peaked 2 days after infection. After intracutaneous injection of
a dose of 10 or 100 µg of aMIP-2 IgG once a day on days 0 and 1, neutrophil counts in BALF on day 2 were reduced to 49 or 37%, respectively, of the value in the control infected mice administered anti-protein A IgG. The antibody administration also improved lung
pathology without affecting virus replication. Furthermore, by
prolonged administration with a higher or lower dose for up to 5 days,
body weight loss became slower and finally 40% of mice in both
treatment groups survived potentially lethal pneumonia. These findings
suggest that MIP-2-mediated neutrophil infiltration during the early
phase of infection might play an important role in lung pathology.
Thus, MIP-2 was considered to be a novel target for intervention
therapy in potentially lethal influenza virus pneumonia in mice.
| |
TEXT |
In influenza virus infection in mice
via the intranasal route, a typical pathological feature is the
presence of areas of lung surface consolidation, which is one kind of
lung injury accompanied by extensive inflammatory infiltration and
hemorrhage (20). It has been suggested that hyperreaction of
the host defense system is involved in the pathogenesis of
consolidation and that morbidity and mortality are immunopathological
consequences (12, 22). Toms et al. (26) reported
that the inflammatory response in the upper respiratory tract after
intranasal infection of ferrets with influenza A virus consisted of
90% neutrophils 1 day after infection. Thus, neutrophil infiltration
during the early phase of infection is considered to be a
characteristic feature of influenza virus infection (23).
Several studies (5, 18) revealed that influenza virus
infection has the potential to induce the production of chemokines,
many of which have been shown to possess chemotactic activity for
inflammatory and immune effector cells and which may contribute to the
pathogenesis of inflammatory diseases (7, 11, 13). Since the
initial discovery of interleukin-8, a chemokine prototype (29,
30), this cytokine is now classified into two groups,
-chemokines (CXC family) and 
-chemokines (CC family) by a few
structural and functional dissimilarities; -Chemokines especially
show chemotactic activity for neutrophils (8). We now know
that chemokines and their receptors are expressed by a wide variety of
cells under positive or negative regulation of certain cytokines, whose
expression is also regulated by chemokines in specific cells, and
chemokine function extends far beyond chemotactic activity to various
processes such as lymphocyte recruitment, angiogenesis, human
immunodeficiency virus replication, and anti-tumor activity (for
reviews, see references 2 and
21).
We have previously reported (10) that influenza virus
infection could induce the production of macrophage inflammatory
protein 2 (MIP-2), a mouse counterpart of -chemokines
(27), in a mouse infection model in vitro and in vivo. In
addition to killing the invading microbes, neutrophils can also cause
tissue injuries such as lung damage in adult respiratory distress
syndrome and other inflammatory diseases by producing superoxides
or certain enzymes (3, 25). Although Cook et al.
(6) demonstrated that MIP-1, a member of -chemokines,
is an important mediator of inflammatory responses to certain viral
infections such as coxsackievirus-induced myocarditis, the pathological
role of MIP-2 in vivo has not yet been studied. In light of these
facts, we studied the effect of anti-MIP-2 immunoglobulin G (aMIP-2
IgG) on the progression of lethal influenza virus pneumonia in mice.
In this study, an outbred specific-pathogen-free strain of ICR female
mice 4 weeks old (body weight, approximately 17 g) obtained from
SLC Co. Ltd. (Hamamatsu, Japan) was used for infection by intranasal
inoculation of a virus solution containing 4,000 PFU/25 µl (four 50%
lethal doses of virus) of a mouse lung-adapted strain of influenza
A/PR/8/34 (PR8) virus (H1N1 subtype). We initially examined the
kinetics of the MIP-2 concentration and virus yields in lung
homogenates and counted the neutrophils in bronchoalveolar lavage
fluid (BALF). The MIP-2 concentration was assayed by antibody sandwich
enzyme-linked immunosorbent assay in which rabbit unlabeled and
biotinylated aMIP-2 IgG antibodies were used as the capture and
secondary antibodies, respectively, followed by the addition of
peroxidase-coupled streptavidin and substrate for color development, as
described previously (19). For standardization of MIP-2
concentration, MIP-2 was purified from the conditioned medium of
lipopolysaccharide-stimulated RAW264.7 cells (LPS-CM) by aMIP-2
IgG-coupled Sepharose column (19). To obtain hyperimmune
aMIP-2 IgG, a fusion construct of MIP-2 to protein A was used as an
antigen to enable the generation of a sufficiently large antibody
response because of the low molecular weight of MIP-2 itself
(19). Western blot analysis of lyophilized LPS-CM confirmed
that this antibody gave a single band with a molecular weight of 6,000, which was identical to that of purified MIP-2 but different from those
of any influenza virus-coded proteins (15). The number of
neutrophils in BALF was calculated by the formula T × R/100, where T is the total number of cells in
BALF determined in a hemocytometer and R is the rate (%)
of neutrophils in Giemsa-staining BALF cells, as described
previously (16). Virus yield was determined by a plaque
method (17). As shown in Fig.
1, a low level of MIP-2 (500 pg/ml) was
detected immediately after infection (on day 0) as the background
level. However, the MIP-2 level significantly increased to a peak on
day 2 and then sharply decreased, although slightly elevated levels
were maintained until day 5. On day 0, only a low level of macrophages
was detected in BALF (<103 cells/BALF). In correlation
with the increase in MIP-2 concentration, neutrophil counts increased
sharply 2 days postinfection (p.i.) and remained almost the same on the
next day. In such an early phase of infection, neutrophils comprised 70 to 90% of total cells in BALF and the remaining cells were mostly
macrophages. In the next phase of infection, the lymphocyte population
gradually increased from 20 to 50% over time. In contrast to the
kinetics of MIP-2, neutrophil counts remained at the elevated levels,
suggesting that additional chemotactic factors such as leukotriene
B4 might contribute to this phenomenon as if compensating
for the low level of MIP-2 as reported previously (9). As
for virus replication in the lung, the virus titer demonstrated 7 log10 PFU on day 1, reaching the maximal level (almost 8 log10 PFU) on day 2 and then gradually decreasing
thereafter. Thus, the kinetics of the MIP-2 concentration and
neutrophil count could be considered similar to those of virus
replication. As shown in Fig. 2,
histopathological studies of the infected lung obtained on day 2 indicated marked neutrophil infiltration into the intra- and
peribronchial spaces. On day 6 when mice began to die, lung pathology
became more severe, accompanied by massive lymphocyte infiltration and
hemorrhage.
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FIG. 1.
Time-related changes in MIP-2 content, neutrophil count,
and virus yield in the lung after intranasal infection of mice with PR8
virus. MIP-2 content (A) and virus yield (C) in lung tissue homogenate
and neutrophil count in BALF (B) were monitored immediately after
infection (day 0) to 7 days after infection. Each point shows the
mean ± standard deviation (SD) for five mice (SDs indicated by
the error bars).
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FIG. 2.
Histopathological study of lungs from mice infected with
PR8 virus. Lungs were obtained from uninfected mice (A) and from
infected mice on day 2 (B and C) or day 6 after infection (D and E) and
then processed for histopathological staining. Magnifications, ×87 for
panels A, B, and D and ×348 for panels C and E.
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Based on the kinetic studies described above, the cell composition and
virus yield in BALF were compared for the aMIP-2 IgG-treated and
control groups on day 2. Because MIP-2-protein A fusion protein was
used as an antigen to prepare aMIP-2 IgG, rabbit anti-protein A IgG
(Sigma, St. Louis, Mo.) was used for the control group. Ten to 15 mice
were used for each experimental group. When infected mice were treated
twice with intracutaneous injections on days 0 and 1 at a dose of 10 or
100 µg of aMIP-2 IgG or 100 µg of anti-protein A IgG/day/mouse,
neutrophil counts in treated groups decreased significantly in a
dose-dependent manner to 49 and 37% of the control group at doses of
10 and 100 µg/day, respectively (Fig. 3). There were no significant differences
in macrophage and other cell counts, including lymphocytes and
epitheliar cells, among the groups. Consequently, total cell counts in
the treatment groups decreased to 70 and 58% of that of the control
group at doses of 10 and 100 µg/day, respectively. These findings
were verified histopathologically, as shown in Fig.
4. Compared with the lungs of control
mice on day 2 shown in Fig. 2, the lungs of treated mice (100 µg/day)
on the same day showed less neutrophil infiltration around the bronchia
and intrabronchial spaces. The administration of aMIP-2 IgG did not
affect virus yields (Table 1). These
findings suggest that administration of aMIP-2 IgG specifically reduces neutrophil exudation into BALF during the early phase of infection without affecting virus replication. Previous reports have demonstrated that interleukin-8, which belongs to the same chemokine family as
MIP-2, enhances the cytopathic effect and virus replication in
infections with positive-strand RNA viruses such as
encephalomyocarditis virus, but not in infections with negative-strand
RNA viruses such as vesicular stomatitis virus (14).
Conversely, MIP-1, which belongs to another chemokine family, enhances
the growth of negative-strand RNA viruses such as influenza virus but
not that of positive-strand RNA viruses such as coxsackievirus
(6). Thus, our data were considered consistent with these
reports.
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FIG. 3.
Effect of anti-MIP-2 IgG administration on the total
cell count and cell composition in BALF obtained from mice infected
with PR8 virus. Infected mice received intracutaneous injections a
total of two times (on days 0 and 1) with either 100 µg of
anti-protein A IgG (white bar), 10 µg of anti-MIP-2 IgG (checkered
bar), or 100 µg of anti-MIP-2 IgG (black bar) per day per mouse. On
day 2 after infection, the total cell counts and cell compositions of
BALF were examined. Each point shows the mean ± SD for five mice
(SDs indicated by the error bars). An asterisk indicates that the value
was significantly different from the control value (P < 0.01 by unpaired t test).
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FIG. 4.
Effect of anti-MIP-2 IgG administration on lung
histopathology. Infected mice received intracutaneous injections a
total of two times (on days 0 and 1) with 100 µg of anti-MIP-2
IgG/day/mouse. On the second day after infection, the lung was
collected and processed for histopathological staining. Magnifications,
×88 for panel A and ×352 for panel B.
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TABLE 1.
Effect of anti-MIP-2 IgG administration on virus growth
in the lungs of mice infected with a mouse lung-adapted
PR8 virus
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We further studied whether administration of aMIP-2 IgG improved the
survival rate and the body weight loss, which is a sensitive indicator
of the progression of viral pneumonia in mice (24). In this
case, duration of antibody administration was prolonged to 5 days p.i.
based on the kinetics of the MIP-2 concentration (Fig. 1). As shown in
Fig. 5A, control mice began to die on day 5. Thereafter, mortality increased, and all control mice had died by
day 12. In contrast, mice in the treated group receiving high (100-µg/day) or low (10-µg/day) doses began to die on day 6, 1 day
later than the control group, and 40% of mice in both treatment groups
continued to survive until day 14. Survival rates of both treatment
groups were significantly higher than that of control group on day 12 and thereafter. However, there was a tendency toward a slower decrease
in survival rates in the high-dose group compared to that in the
low-dose group between 6 and 10 days p.i. When a dose of 300 µg/day
was used, the survival rates were similar to that of 100 µg/day (data
not shown). The beneficial effect of aMIP-2 IgG administration was also
shown in body weight loss with a clearer dose dependency than that
shown by survival rates. In the control group, body weight successively
decreased from 4 days p.i. By administering a higher dose, body weight
loss ceased between 4 and 6 days p.i. and recovered somewhat in the
subsequent period, demonstrating significantly higher values than those
of control group after as early as 4 days p.i., whereas recovery was
smaller in the low-dose group and significant differences were obtained
only after 10 days p.i. in that group.
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FIG. 5.
Effect of anti-MIP-2 IgG administration on the survival
rate and body weight loss. Infected mice received a total of six
intracutaneous injections once daily for six days (indicated by the six
arrows below the abscissa) with either 100 µg of anti-protein A IgG
(closed circles) (control), 10 µg of anti-MIP-2 IgG (closed
triangles), or 100 µg of anti-MIP-2 IgG (closed squares) per day per
mouse, and the survival rate (A) and body weight (B) of the mice were
monitored. Each point shows the mean ± SD for 10 to 15 mice in
each experimental group (SDs indicated by the error bars). An open
symbol indicates that the value was significantly different from the
control value, with P values of 0.04 (squares) and 0.01 (triangles). The data in panel A were assessed by Fisher's exact
probability test, and the data in panel B were assessed by unpaired
t test.
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It has been demonstrated that both nitric oxide (NO) and active oxygen
radicals are involved in the pathogenesis of influenza virus-induced
pneumonia in mice (1, 20). It is well-known that these
tissue-toxic molecules are produced by neutrophils, especially
chemokine-attracted neutrophils (3, 8, 16, 25). Although the
correlation between pyrexia and neutrophil response was shown in
influenza A virus infections of animal models (26), the
pathological role of MIP-2-mediated neutrophil exudation has not yet
been clarified. Several studies demonstrated that the use of antibody
against chemokines leads to prevention or attenuation of certain acute
inflammatory diseases in animal models due to reduction of neutrophil
infiltration (4, 8, 28). It has been shown that the ability
of neutrophils to produce active oxygen radicals is significantly
reduced after the chemokine is blocked by the antibody (4).
Leukotriene B4 is known to enhance NO synthesis in
neutrophils (16) and reported to be induced actually in a
later phase of influenza virus infection in mice (9).
Indeed, when NO contents in BALF from infected mice were measured by an
automated NO detector-high-pressure liquid chromatograph system, these
values did not significantly differ between the untreated control group
and groups treated with aMIP-2 IgG (unpublished data). Taking these
facts together with our findings, it is suggested that administration
of aMIP-2 IgG might partially eliminate the tissue-toxic activity of
these radical molecules by the reduction of neutrophil exudation,
resulting in attenuation, but not complete prevention, of lung tissue
injury. However, it is evident that MIP-2 plays an important
pathological role and thereby is considered a novel target for
intervention therapy in influenza virus-induced pneumonia.
| |
ACKNOWLEDGMENTS |
This study was supported in part by a grant for research into
traditional medicine from the Tokyo Metropolitan Government.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Human Science, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan. Phone: 81 076-434-2281, ext. 2415. Fax: 81 076-434-5186. E-mail:
ochiai{at}ms.toyama-mpu.ac.jp.
| |
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Journal of Virology, March 2000, p. 2472-2476, Vol. 74, No. 5
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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