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Previous Article | Next Article 
Clinical and Diagnostic Laboratory Immunology, November 1999, p. 891-894, Vol. 6, No. 6
1071-412X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Can an Antibiotic (Macrolide) Prevent
Chlamydia pneumoniae-Induced Atherosclerosis in a
Rabbit Model?
Ignatius W.
Fong,1,*
Brian
Chiu,1
Esther
Viira,1
Dan
Jang,2
Michael W.
Fong,1
Rosanna
Peeling,3 and
James B.
Mahony2
Departments of Medicine, Laboratory Medicine
and Pathology, St. Michael's Hospital, University of Toronto,
Toronto,1 and Department of Pathology
and Molecular Medicine, St. Joseph's Hospital, McMaster University,
Hamilton,2 Ontario, and LCDC Chlamydia
Laboratory, Winnipeg, Manitoba,3 Canada
Received 14 April 1999/Returned for modification 21 May
1999/Accepted 1 September 1999
 |
ABSTRACT |
There is increasing data implicating Chlamydia
pneumoniae in the pathogenesis of atherosclerosis, and
antibiotics may theoretically be useful to prevent secondary vascular
complications. Three groups of New Zealand White specific-pathogen-free
rabbits, fed cholesterol-free chow, were inoculated via the nasopharynx
on three occasions, 2 weeks apart, with C. pneumoniae.
Group I (n = 23) rabbits were untreated; group II
(n = 24) rabbits were treated with azithromycin at 30 mg/kg of body weight daily for 3 days and then once every 6 days,
starting 5 days after first inoculation and continuing until sacrifice
(early treatment); and group III (n = 24) rabbits were
treated with the same dose of azithromycin but initiated 2 weeks after
the last inoculation. All animals were sacrificed at 10 to 11 weeks
after initial inoculation and examined for signs of atherosclerosis of
the aorta. Eight (34.8%) untreated rabbits developed early signs of
atherosclerosis, whereas only one (4.2%) in the early-treatment group
had such signs (P = 0.02). However, eight rabbits
(33.3%) of the delayed-treatment group had atherosclerotic changes of
the aorta and no significant reduction compared to untreated rabbits.
Early treatment of C. pneumoniae-infected rabbits with
azithromycin was highly effective (87%) in preventing atherosclerotic changes, but delayed treatment was ineffective. It is possible that
longer or more aggressive antibiotic treatment may be needed to reverse
preformed lesions or that antibiotics may not be of value once lesions
have formed.
| |
INTRODUCTION |
Chlamydia pneumoniae, a
respiratory pathogen in humans, has been associated with coronary heart
and carotid artery diseases in many seroepidemiological studies
(6, 17, 20, 21, 24, 28, 29, 32, 33). Moreover, the organism
can be detected in fatty streaks and atheromatous plaques from the
aorta and coronary, carotid, and femoral-popliteal arteries but not in
normal vessels (1, 2, 4, 13-15, 31). Viable organisms have
also been recovered from atheromas of carotid and coronary arteries
(12, 18, 26).
Further evidence of the role of C. pneumoniae in
atherogenesis is supported by animal models with rabbits reported by us
and others (7, 16, 23). Recently, two small pilot clinical trials have suggested that newer macrolides (which are effective in
vitro against C. pneumoniae) may decrease secondary
cardiovascular events after myocardial infarction or unstable angina
(9, 10).
It is important, however, to determine whether antimicrobial agents are
of value in preventing or reversing early aortic lesions that are
inducible in the rabbit model with C. pneumoniae. These studies may provide insight into and guidance on the potential dosages
and duration of therapy for future clinical trials in humans.
| |
MATERIALS AND METHODS |
This study was approved by the Animal Care Committee of our
institution, and guidelines for care of the animals were strictly adhered to.
Animals.
One-month-old, male, New Zealand White,
specific-pathogen-free rabbits, fed standard chow (no cholesterol
supplementation), were used in the experiments. Three groups of animals
(24 per group) were inoculated via the nasopharynx with a small
catheter on three separate occasions, 2 weeks apart, with C. pneumoniae. Group I rabbits were untreated (controls); group II
received azithromycin at 30 mg/kg of body weight daily for 3 days and
then once every 6 days, starting after the 5th day post-initial
inoculation and continuing until sacrifice; and group III received the
same dosage schedule of azithromycin but start 2 weeks after the last
inoculation. Animals were sacrificed and aortas were examined for signs
of atherosclerosis 10 to 11 weeks after initial inoculation.
C. pneumoniae strains and inoculum.
TWAR strain
AR-39 (Seattle, Wash.) and ATCC strain VR 1310 (originally respiratory
isolates) were used in the studies. The organisms were grown in HEp-2
cells (27). Infected cells were harvested with sterile glass
beads and ultrasonic disruption after 72 h. Cell culture-grown
organisms were partially purified by one cycle each of low- and
high-speed centrifugation, resuspended in sucrose-phosphate-glutamic
acid buffer, and frozen in 1.0-ml aliquots at 
70°C. Inoculum
preparations were adjusted to contain 1.5 × 107 to
2.6 × 107 inclusion-forming units of C. pneumoniae. Contamination by Chlamydia trachomatis,
Chlamydia psittaci, or Mycoplasma species was
excluded by analysis with PCR genus- and species-specific primers
(26) and monoclonal antibody staining.
Serology.
Antibodies (immunoglobulin G [IgG]) to C. pneumoniae were measured by the microimmunofluorescence test (MRL
Diagnostics, Cypress, Calif.). The IgG serum antibody fractions were
measured by using fluorescein-isothiocyanate-conjugated goat
anti-rabbit IgG (Jackson Laboratories, West Grove, Pa.). Blood was
obtained from the earlobe marginal veins on the day of sacrifice. Our
previous studies of 36 rabbits showed no detectable C. pneumoniae antibodies at baseline before inoculation. IgM and IgA
antibodies were not tested because anti-rabbit IgM and IgA conjugates
were not available commercially. The C. pneumoniae
antibodies were tested in all three groups by screening at a 1:16
dilution against purified elementary bodies of C. pneumoniae
(AR-39). All serum samples positive at 1:16 had their titers determined
in twofold dilutions to end point.
Pathology.
At sacrifice, the entire aorta from the ascending
aorta to the iliac bifurcation was removed and cleansed of any fat. The aorta was split longitudinally, and sections were taken from the arch
and descending and abdominal aorta.
All specimens obtained were fixed in 10% buffered formalin, processed,
and paraffin embedded. Staining with hematoxylin and eosin stain and an
elastic stain (Movat's pentachrome) was performed on sections for
histological examination. Aortic lesions were graded histologically,
modified from the work of Daley et al. (5), as follows:
grade I, early fatty streaks, defined as consisting of foamy cells in
the intima; grade II, advanced fatty streaks, defined as consisting of
approximately equal numbers of foamy cells and spindle-shaped cells;
grade III, spindle cell lesion, defined as consisting of spindle-shaped
(smooth muscle) cells and other products; grade IV, advanced
atheromatous lesion, defined as the presence of a core containing pools
of extracellular lipid and/or necrotic debris and fibrous cap.
Calcification of a fibromuscular lesion without a lipid core was also
classified as grade IV. None of the infected rabbits developed the
classic grade IV lesion with a lipid core, but rather they had
fibromuscular lesions with calcification.
Myxoid lesions were defined as isolated thickening of the intima-media
with ground substance or myxoid-like material which stained green with
Movat's stain but had no other features of atherosclerosis as defined.
These lesions were usually associated with fragmentation and separation
of the elastic fibers in the media. Periaortitis represented focal
areas of accumulation of inflammatory mononuclear cells between the
outer wall of the aorta and the adventitia. These cells consisted of
macrophages and T and B lymphocytes, shown by immunohistochemical
staining with specific monoclonal antibodies.
Immunohistochemical study.
Immunohistochemical staining
(14) for C. pneumoniae antigen was performed on
paraffin-embedded sections by the labelled strept
avidin-biotin-peroxidase method (3) with the Histo-Stain kit
of Zymed. The antibodies used included C. pneumoniae-specific monoclonal antibody RR-402 and
Chlamydia genus-specific antibody CF-2 (Washington Research
Foundation, Seattle), and a second C. pneumoniae-specific
monoclonal antibody, Chlamydia Cel Pn (Cell Lab). In selected cases,
assays with factor VIII and smooth muscle actin (DAKO, Carpinteria,
Calif.) and T cells, B cells, and macrophage markers specific for
rabbits (Serotec) were performed on adjacent sections to identify cells
of endothelium, smooth muscle, T and B cells, and macrophages, respectively.
A negative control consisting of phosphate-buffered saline instead of
primary antibodies was used in each run. Positive controls for C. pneumoniae included positive lung and spleen cells from our
previous study (7), and cell pellets of the C. pneumoniae inoculum prepared in HEp-2 cells were fixed in formalin
and embedded in paraffin.
Data analysis.
The prevalence of atherosclerotic lesions in
the treated groups was compared to that in the untreated group by
chi-square analysis or Fisher's exact test.
| |
RESULTS |
One of the control untreated animals was sacrificed early because
of an accident and was not included in the analysis. Eight (34.8%) of
the 23 untreated rabbits had early signs of patchy atherosclerosis
(predominantly grade III lesions). Another five (21.7%) rabbits had
myxoid-like material accumulating between the intima-media but no other
changes suggestive of atherosclerosis. Eight (34.8%) rabbits
demonstrated focal mononuclear cell infiltration in the adventitia of
the abdominal aorta classified as periaortitis (Fig.
1).
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|
FIG. 1.
(A) Myxoid ground substance accumulation and elastic
fragmentation in intima-media (arrowheads indicate adjacent grade III
lesion). Movat's stain was used. (B) Grade III lesion with C. pneumoniae demonstrated by immunohistochemistry (area indicated by
arrowheads). (C) Periaortitis, infiltration of aortic adventitia by
lymphocytes and macrophages (indicated by star) and unremarkable intima
(arrowheads indicate internal elastic lamina).
|
|
The effects of the azithromycin treatment on the various pathological
entities are summarized in Table 1. Early
treatment with azithromycin was highly effective in preventing early
atherosclerotic lesions (87%) and periaortitis (100%) but had no
effect on the myxoid-like changes. Delayed treatment was ineffective in
reducing or reversing atherosclerotic lesions and myxoid-like changes
but was highly effective in reducing periaortitis (100%). The results of the immunostaining for C. pneumoniae antigen are
summarized in Table 2. Azithromycin did
not decrease the prevalence of detectable antigen between the untreated
controls and early-treated rabbits, but C. pneumoniae was
detected more frequently in the delayed-treatment group than in the
early-treatment group.
Serology.
All animals in the control untreated group had
antibodies to C. pneumoniae at a >1:16 dilution (range,
1:32 to 1,024) and one (4.2%) of the animals in the early-treated
group had positive serology of 1:16, but antibodies in the rest were
undetectable (<1:16). Six (25%) of the animals in the
delayed-treatment group had undetectable antibodies, but the remaining
18 (75%) had antibodies ranging from a 1:16 to a 1:256 dilution. None
of the rabbits with undetectable antibodies had evidence of aortic lesions.
| |
DISCUSSION |
We have previously shown that C. pneumoniae infection
in the rabbit can induce early lesions of atherosclerosis de novo,
whereas these changes are not seen with sham-infected controls or
Mycoplasma pneumoniae-infected rabbits (20, 29).
This study clearly demonstrates that early treatment with azithromycin,
5 days after initial infection, was highly effective (87%) in
preventing atherosclerosis-like lesions or periaortitis. The
significance of the periaortitis and myxoid-like changes are not clear,
and we cannot explain the reason why the myxoid lesions were not
decreased with treatment but periaortitis was prevented. Myxoid or
ground substance (glycosaminoglycan) accumulation is commonly seen in
human atherosclerotic lesions (preatheroma and more advanced lesions)
but may also be present in Marfan's syndrome and vascular inflammation
(30, 34). This is believed to be a response of smooth muscle
cells to inflammatory stimuli, with increased production of
glycosaminoglycan. Since we did not analyze the biochemical nature of
our lesions, we can only assume that they are similar based on the
histochemical staining (Movat's stain). Delayed treatment (6 weeks
after initial infection) was ineffective in reducing or reversing early
atherosclerotic lesions but still effective (100%) in preventing
periaortitis. Treatment with the macrolide did not significantly
decrease the prevalence of C. pneumoniae antigen in the
aorta. Detectable antigen in the aorta was more frequently localized to
atherosclerosis-like lesions or areas of periaortitis but could be seen
in areas without histological changes. Although not all lesions with
atherosclerotic changes demonstrated C. pneumoniae antigen,
this could be related to sampling at a specific microscopy level.
However, we could not determine whether there were viable organisms, as
C. pneumoniae is extremely difficult to recover by culture
from rabbits and can be recovered only from the respiratory tract
within 2 to 3 days of inoculation (22).
The results of the C. pneumoniae serology assay showed that
early treatment was largely effective in abrogating the antibody response (and was correlated with lack of aortic lesions), compared to
delayed treatment. This would suggest that the antigens detectable in
the early-treated group represent nonviable bacteria or existence in a
latent stage without stimulation of the immune system.
In a study of different design, Muhlestein et al. (23) were
able to show that azithromycin at 30 mg/kg intramuscularly daily for 1 week and then twice weekly for another 6 weeks (starting 3 days after
final triple inoculation of C. pneumoniae) was able to
reverse the enhanced intimal thickening of the aortas in the rabbits
fed a 0.25% cholesterol-enriched chow. Our study did not use a
cholesterol-enriched diet and therefore, it looked at the de novo
effect of C. pneumoniae infection on induction of early atherosclerosis. Moreover, in our study the animals were treated by
oral gavage with less frequent dosing.
Azithromycin, a newer macrolide antibiotic of the azalide subclass, has
in vitro activity against C. pneumoniae similar to that of
erythromycin with a MIC against 90% of strains of 0.125 to 0.25 µg/ml (11). Although the absolute bioavailability is only
37%, this drug penetrates intracellularly in a wide variety of tissues
(including macrophages where C. pneumoniae may reside), with
an intracellular concentration of 200 to 500 times the levels in plasma
or extracellular levels (25). The dosage used in our study
was designed to mimic the human dose of 500 mg once a week being used
in an ongoing clinical trial (WIZARD study). Azithromycin has a long
terminal half-life of 63 h in humans, allowing once-a-week dosing,
and a slightly shorter half-life in rabbits (24a). It is
possible that with more frequent dosing and longer therapy we may have
greater efficacy with the delayed treatment. But it is also possible
that we may not be able to reverse preformed atherosclerotic lesions,
as we previously showed that grade I to III lesions can be formed
within a month of C. pneumoniae infection in rabbits
(7). Since in the delayed-treatment group the rabbits received at least 4 to 5 weeks of therapy without benefit, and the
normal lifespan of a rabbit is 7 to 8 years, 10-fold less than that of
humans, this would suggest that short-term therapy in humans may not be
effective and that clinical trials should use a longer duration, of
more than 40 to 50 weeks of treatment, to assess the clinical benefit
of azithromycin in vascular complications of atherosclerosis.
| |
ACKNOWLEDGMENTS |
This study was funded by a grant from Pfizer Inc.
We are grateful to D. Bajhan for her assistance in preparing the manuscript.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Division of
Infectious Diseases, St. Michael's Hospital, 30 Bond St., Room 4-179V, Toronto, ON M5B 1W8, Canada. Phone: (416) 864-5746. Fax: (416) 864-5310. E-mail: fongi{at}smh.toronto.on.ca.
| |
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Clinical and Diagnostic Laboratory Immunology, November 1999, p. 891-894, Vol. 6, No. 6
1071-412X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
