From the Departments of Neurosurgery (K.Y., H.I.), Microbiology (M.S.,
T.N.), and Pathology (T.G.), Yamaguchi University School of Medicine,
Yamaguchi, Japan, and the Department of Pediatrics, Saiseikai Shimonoseki
General Hospital (K.O.), Shimonoseki, Japan.
Correspondence to Katsuhiro Yamashita, Department of Neurosurgery, Yamaguchi University School of Medicine, 1144 Kogushi, Ube, Yamaguchi, 755 Japan. E-mail yamasita-ygc{at}umin.u-tokyo.ac.jp
Methods—Twenty carotid atherosclerotic lesions that were resected
during carotid endarterectomy were investigated.
Parallel sections were stained immunohistochemically with monoclonal
antibodies for a C pneumoniae–specific antigen,
macrophages, and smooth muscle cells.
Results—Immunoreactivity for the C
pneumoniae–specific antigen was observed in 11 of 20 specimens
(55%), and intense immunoreactivity was observed in 7 of 20 (35%).
C pneumoniae infection was observed in
endothelial cells, macrophages and in smooth
muscle cells that had migrated into the atheromatous
plaque, as well as in smooth muscle cells and small arteries in the
media underlying the atheromatous plaques. C
pneumoniae infection was most prominently observed in smooth
muscle cells. The severity of the infection as demonstrated by
immunohistochemistry was not significantly related to general risk
factors for atherosclerosis.
Conclusions—C pneumoniae widely infects
endothelial cells, macrophages, and smooth
muscle cells in the atherosclerotic carotid artery. The results of the
present study can help us to understand how C
pneumoniae infection contributes to the progression of carotid
atherosclerosis.
Recently, C pneumoniae has been linked to an
atherosclerotic disease. Since Saikku et al3 first reported
that chronic C pneumoniae infection is a risk factor for
coronary heart disease, a number of investigations have shown a
positive relationship between C pneumoniae infection and
atherosclerosis.4 5 6 7 8 9 10 11 12 13 14 Shor et
al9 detected by electron microscopy bodies of C
pneumoniae in lipid-rich areas of fibrous plaques and in
intimal smooth muscle cells of the coronary arteries. The
organism has also been detected in atherosclerotic lesions by
immunohistochemistry, the polymerase chain reaction method, and cell
culture.10 11 12 13 14 15 Moreover, the presence of C
pneumoniae in carotid atherosclerotic lesions and its possible
contribution to ischemic cerebrovascular diseases have been
reported.16 17 18 However, the detailed distribution of
C pneumoniae infection in the carotid
arterial wall and atheromatous plaque
remains to be elucidated. The distribution of C
pneumoniae infection may indicate how it contributes to the
progression of atherosclerotic lesions.
The aim of the present study was to clarify the distribution of
C pneumoniae infection in carotid arterial
walls and atheromatous plaques, which were resected
during carotid endarterectomy (CEA) by
immunohistochemistry, with use of monoclonal antibodies for a C
pneumoniae–specific antigen, macrophages, and smooth
muscle cells. In addition, we investigated the relationship between the
severity of the infection, as demonstrated by immunohistochemistry, and
general risk factors for atherosclerosis.
Immunohistochemical Staining for C pneumoniae
Infection and Identification of Cell Types With
Infection
In Situ End Labeling of Fragmented DNA (TUNEL Staining)
Risk Factors
Statistical Analysis
Cells with AY-6 immunoreactivity were observed both in the intima near
the atheromatous plaque and in the media, which was
partially removed during the CEA procedure. The border between the
intima and the media was clearly demonstrated by elastica–van Gieson
staining. AY-6 immunoreactivity was observed in
endothelial cells of the intima near the
atheromatous plaque (Fig 1
The immunoreactivity for Virostat 1641 (a C
trachomatis–specific monoclonal antibody) was not observed in the
atheromatous plaque or in the media of any of the
specimens. Only a few scattered TUNEL-positive cells were seen in the
subendothelial region of the
atheromatous plaques in two specimens with intense AY-6
immunoreactivity (data not shown).
The risk factors for atherosclerosis of each patient
are shown in Table 1
We demonstrated that C pneumoniae infected both the intima
near an atheromatous plaque and the media of the
carotid artery. Infection was localized to endothelial
cells in the intima and to macrophages and smooth muscle cells
in the atheromatous plaque. This finding is similar to
those reported for in vivo studies of an aorta and a coronary
artery and in vitro studies,9 10 11 13 19 20 21
although this is the first report of the infection in
endothelial cells in vivo. Macrophage seem to
play an important role in the transportation of C pneumoniae
bodies and progression of atherosclerosis. It is
thought that C pneumoniae is taken up by macrophages
in the pharynx or the lung after a chronic infection and transported
via the blood to the subendothelial region through the
injured endothelium of the
artery.22 23 According to the hypothesis of
Ross,24 macrophages in the intima produce
some cytokines and growth factors (such as platelet-derived
growth factor) and elicit migration of smooth muscle cells from the
media to the intima, as well as an inflammatory response that
subsequently leads to the progression of
atherosclerosis. Chlamydial organisms
survive and multiply in macrophages,25 26
and such a chronic infection of C pneumoniae in
macrophages is believed to enhance the proliferative and
inflammatory processes of atherosclerosis by inducing
some cytokines and
lipoproteins.27 28 29 30
Infection by C pneumoniae was observed not only in smooth
muscle cells that had migrated into the atheromatous
plaque but also in smooth muscle cells in the media underlying the
atheromatous plaques. The susceptibility of smooth
muscle cells to C pneumoniae infection has been demonstrated
in previous in vitro studies.19 20 21 The outcome
of widespread infection of C pneumoniae in smooth muscle
cells is unclear compared with that in macrophages. Growth
factors such as platelet-derived growth factor in atherosclerotic
lesions are also produced and released by smooth muscle
cells,31 32 33 and this function of smooth muscle
cells may be enhanced by chronic C pneumoniae infection.
Infection by C pneumoniae of the wall of small arteries in
the media is interesting. It is generally believed that the C
pneumoniae body is transported to the carotid arterial
wall and the atheromatous plaque predominantly by
macrophages that can pass through injured
endothelium. However, another route of infection, in
which C pneumoniae invades an atheromatous
plaque and carotid arterial wall from small arteries in the
media (vasa vasorum), is possible.
Recently, many investigations34 35 36 37 38 have shown
the involvement of apoptosis of both macrophages and
smooth muscle cells in atherosclerosis. Although TUNEL
staining can cause overestimation of apoptosis, some cells in
the atherosclerotic lesions surely undergo apoptotic cell
death, and in addition, bacterial infection is a well known cause of
apoptosis.39 However, only a few
TUNEL-positive cells were observed in the atheromatous
plaques in the present study, which is consistent with
other reports35 38 ; thus, there was a
considerable discrepancy between the number of TUNEL-positive cells and
the number of cells infected by C pneumoniae. The
relationship between atherosclerosis and C
pneumoniae infection probably does not involve the process of
apoptosis.
We investigated well-characterized general risk factors for
atherosclerosis (hypertension,
hypercholesterolemia, diabetes, and cigarette
smoking) for each patient, and none of these risk factors was related
to the severity of C pneumoniae infection as demonstrated by
immunohistochemistry, even though hypertension was observed in 74% of
patients. This result is similar to those reported in previous studies
of C pneumoniae infection of the coronary
artery7 14 and does not support a positive
relationship between C pneumoniae infection and
atherosclerosis. However, some serological
investigations of C pneumoniae infection have provided
evidence for a significant relationship between infection and
atherosclerosis based on the correction of general risk
factors for
atherosclerosis.4 5 7 16
Therefore, C pneumoniae infection can be related to carotid
atherosclerosis independently of the general risk
factors and will become the next risk factor for
atherosclerosis.
In conclusion, we investigated the distribution of C
pneumoniae infection in atherosclerotic carotid lesions resected
during CEA. Infection by C pneumoniae was widespread in
endothelial cells, macrophages, and smooth
muscle cells that had migrated into the atheromatous
plaque. In addition, smooth muscle cells and small arteries in the
media of the carotid artery were also infected. This investigation has
not necessarily established the etiologic role of C
pneumoniae infection in the development of
atherosclerosis, and further studies are required to
confirm all of Koch's postulates, which establish the etiologic role
of C pneumoniae infection in
atherosclerosis.40 However,
clinical evidence that C pneumoniae infection contributes to
atherosclerosis is
accumulating,41 42 and an animal model of C
pneumoniae infection in the atherosclerotic lesion has been
developed.23 The demonstration of the
distribution of C pneumoniae infection in the present
study, together with the animal model of C pneumoniae
infection, will help to clarify how C pneumoniae infection
contributes to the progression of carotid atherosclerotic lesions.
Received November 18, 1997;
revision received January 12, 1998;
accepted January 12, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Distribution of Chlamydia pneumoniae Infection in the Atherosclerotic Carotid Artery
Abstract
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Background and
Purpose—Chlamydia pneumoniae infection has
recently become noteworthy in relation to
atherosclerosis. We investigated by
immunohistochemistry the distribution of C pneumoniae
infection in the atherosclerotic carotid artery.
Key Words: atherosclerosis • carotid arteries • Chlamydia pneumoniae • infection
Introduction
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Chlamydia pneumoniae, a gram-negative
bacteria, frequently causes community-acquired respiratory infections,
such as pharyngitis and pneumonia. There are epidemics of C
pneumoniae infection every 5 to 7 years, with 50% to 70%
prevalence of seropositivity in adults, and most adults are infected 2
to 3 times in their lifetime.1 2
Materials and Methods
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Twenty specimens of carotid atheromatous plaque
were obtained during CEAs performed in 19 patients with
symptomatic severe (>70%) carotid artery
stenosis. The severity of carotid artery stenosis in
these patients was verified by conventional carotid angiography. The
symptoms of patients were transient ischemic attacks in 8 of 19
and minor stroke in 11 of 19 patients. The specimens were embedded in
paraffin after fixation with 10% buffered formaldehyde and cut
serially to expose coronal planes of the carotid artery and
atheromatous plaque. Eight serial sections 6 µm
thick were prepared from each specimen for the following:
hematoxylin-eosin staining, elastica–van Gieson staining to visualize
elastic fibers, immunohistochemical staining, and terminal
deoxynucleotidyltransferase-mediated
dUTP nick end labeling (TUNEL) staining to detect apoptotic
cells.
Three parallel sections of each specimen were
immunohistochemically stained with the following monoclonal antibodies:
CF-2, a Chlamydia genus–specific monoclonal antibody that
recognizes Chlamydial lipopolysaccharide (Washington
Research Foundation) diluted 1:1000; AY-6, a C
pneumoniae–specific monoclonal antibody that recognizes a 53-kDa
outer membrane protein (Hitachi Chemical), diluted 1:1000; and Virostat
1641, a C trachomatis–specific monoclonal antibody that
recognizes a major outer membrane protein (Virostat), diluted 1:100.
Another two parallel sections from each specimen were also
immunohistochemically stained to identify the cell types infected by
C pneumoniae, with two monoclonal antibodies: anti-human
-smooth muscle actin (DACO), diluted 1:50, and anti-human
macrophage KP-1 (DACO), diluted 1:10. The immunoreactivity was
detected by immunoperoxidase staining through use of the
streptavidin-biotin-peroxidase method (LSAB kit; DACO) and was
visualized with diaminobenzidine tetrahydrochloride as the chromogen.
Control slides with HEp-2 cell monolayers infected with C
pneumoniae or C trachomatis were processed in parallel
with the tissue sections. Finally, sections were counterstained with
hematoxylin. Immunoreactivity for C pneumoniae infection was
assessed in the whole area of each section according to the following
four grades: 3+, intense immunoreactivity in numerous cells; 2+,
positive immunoreactivity in a moderate number of cells (10 to 100
cells); 1+, weak immunoreactivity in a few cells; and 0, no
immunoreactivity.
TUNEL staining was performed with use of an in situ
apoptosis detection kit (ApopTag Plus; Oncor Inc) to detect
cells with DNA fragmentation. Briefly, deparaffinized sections were
incubated with 20 µg/mL proteinase K for 15 minutes at room
temperature to digest the proteins in the specimens, washed with water,
and treated with 2% vol/vol hydrogen peroxide for 5 minutes to
extinguish the endogenous peroxidase activity. Immediately
afterward, the sections were washed with distilled water and immersed
in equilibration buffer, then in terminal
deoxynucleotidyltransferase enzyme
solution for 1 hour at 37°C, followed by stop/wash buffer.
Subsequently, 35 µL anti-digoxigenin-peroxidase solution was applied
to each slide, and peroxidase was detected by staining with 0.025%
wt/vol diaminobenzidine. Sections were finally counterstained with
hematoxylin. Negative controls were treated with distilled water
instead of the terminal
deoxynucleotidyltransferase enzyme.
The general risk factors for atherosclerosis,
smoking, hypertension, hypercholesterolemia,
diabetes mellitus, and complications of ischemic heart diseases
were investigated for each patient. The severity of each risk factor
was graded as follows: current smoker (>20 cigarettes/day), former
smoker, and never smoked; with hypertension and without hypertension;
severe hypercholesterolemia of >250 mg/dL,
moderate hypercholesterolemia of 220 to 250
mg/dL, and no hypercholesterolemia; severe
diabetes mellitus with systemic complications such as retinal and renal
diseases, moderate diabetes mellitus without systemic complications,
and no diabetes mellitus.
The relationship between immunoreactivity for C
pneumoniae infection in the atherosclerotic carotid artery and
general risk factors for atherosclerosis was
investigated using multiple regression analysis, and a value of
P<.05 was considered to indicate statistical
significance.
Results
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
The intensity of CF-2 (a Chlamydia genus–specific
monoclonal antibody) immunoreactivity was the same as that of AY-6 (a
C pneumoniae–specific monoclonal antibody) in all
specimens. Eleven of 20 specimens (55%) were positive for CF-2 and
AY-6 immunoreactivity, and intense AY-6 immunoreactivity (grade 3) was
observed in 7 of 20 specimens (35%) (Table 1
).
View this table:
[in a new window]
Table 1. Immunoreactivity for CF-2, AY-6, and Virostat Monoclonal
Antibodies in the Atherosclerotic Carotid Artery and Risk Factors for
Atherosclerosis in 19 Patients ). Within the
atheromatous plaque, macrophages and smooth
muscle cells that had migrated from the media into the plaque showed
AY-6 immunoreactivity (Figs 2 and 3); cells with AY-6 immunoreactivity were
identified by immunohistochemical staining of adjacent sections for
KP-1 and -smooth muscle actin. Macrophages with C
pneumoniae infection were predominantly located in the
subendothelial region. Numerous cells with AY-6
immunoreactivity observed in the media were smooth muscle cells
underlying the atheromatous plaques as well as those of
small arteries that supply the carotid arterial wall (Figs 4 and 5).
These smooth muscle cells were also identified by immunohistochemistry
for -smooth muscle actin. The cells with C pneumoniae
infection formed clusters that were distributed in a patchy pattern in
the atheromatous plaque and the media.
View larger version (142K):
[in a new window]
Figure 1. Case 2. AY-6 (a C
pneumonia–specific monoclonal antibody) immunoreactivity in
endothelial cells (arrows). Weak immunoreactivity was
also observed in form cells in the intima (below the arrows) (original
magnification x100, bar=50 µm).
View larger version (157K):
[in a new window]
Figure 2. A, AY-6 immunoreactivity in cells within an
atheromatous plaque (case 8) (original magnification
x56; bar=100 µm). B, Immunohistochemical staining for KP-1 to
detect macrophages in the section adjacent to that shown in
panel A. Many KP-1 positive cells were scattered throughout the
atheromatous plaque with a distribution similar to that
for AY-6 (original magnification x56; bar=100 µm).
View larger version (84K):
[in a new window]
Figure 3. A, Coronal view of the
atheromatous specimen of case 12 (hematoxylin-eosin
staining; original magnification x10; bar=400 µm). The area in
the thickening intima, which is surrounded by arrowheads, is magnified
in panels B and C. B, Immunohistochemical staining for -smooth
muscle actin to detect smooth muscle cells. Smooth muscle cells that
had migrated were located in the atheromatous plaque in
the intima (original magnification x50; bar=50 µm). C, AY-6
immunohistochemical staining (original magnification x50; bar=50
µm). The distribution of the AY-6 positive cells is similar to that
for -smooth muscle actin as shown in panel B.
View larger version (138K):
[in a new window]
Figure 4. A, Coronal view of the
atheromatous specimen of case 12 (hematoxylin-eosin
staining; original magnification x25; bar=200 µm). The area in
the media, which is shown below the arrowheads, is magnified in panel
B. B, AY-6 immunohistochemical staining. AY-6 immunoreactivity was
observed in numerous smooth muscle cells in the media underlying the
atheromatous plaques (original magnification x50;
bar=75 µm).
View larger version (145K):
[in a new window]
Figure 5. AY-6 immunoreactivity in small arteries in the
deep media underlying the atheromatous plaques. The
immunoreactivity was observed in endothelial cells and
in smooth muscle cells of small arteries (arrows) (original
magnification x50; bar=100 µm). 
. The positivity of each risk factor for all 19
patients was 31.6% (6 of 19) for smoking, 73.7% (14 of 19) for
hypertension, 31.6% (6 of 19) for diabetes, and 10.5% (2 of 19) for
hypercholesterolemia. Ischemic heart
disease was present in 3 of 19 patients (15.8%). None of these
risk factors correlated significantly with AY-6 immunoreactivity, that
is, with the severity of C pneumoniae infection.
Discussion
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
In the present study, C pneumoniae infection of the
carotid arterial wall and the atheromatous
plaque was observed in 55% of the patients. Although this frequency of
infection is very similar to those reported in other
studies,9 10 11 13 14 C pneumoniae
infection was not observed in all our patients. It is more likely that
the results of the histopathologic examination underestimate rather
than overestimate the frequency of C pneumoniae infection,
because only a very small region with a 6-µm thickness of each
atherosclerotic lesion was examined.
Acknowledgments
We thank Dr Shiro Kashiwagi and Dr Shoichi Kato for helpful
discussions in preparation of the manuscript and Fumio Iwasaki for his
technical assistance in immunohistochemistry. We also thank the doctors
in the departments of neurosurgery of Ube Kosan Central Hospital,
Saiseikai Yamaguchi General Hospital, and National Yamaguchi Hospital
for providing the carotid atheromatous plaque used in
our study.
References
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
, IL-1ß, and IL-6 by human monocytes.
Proc Eur Soc Chlamydia Res. 1992;2:85.
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