Previous Article | Next Article 
Infection and Immunity, May 2001, p. 3460-3465, Vol. 69, No. 5
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.5.3460-3465.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Assessing Vascular Permeability during Experimental
Cerebral Malaria by a Radiolabeled Monoclonal Antibody
Technique
Henri C.
van der
Heyde,1,2,*
Philippe
Bauer,3
Guang
Sun,2
Wun-Ling
Chang,4
Lijia
Yin,4
John
Fuseler,4,5 and
D. Neil
Granger3
Departments of Microbiology and
Immunology,1 Cellular and Molecular
Physiology,3 and
Medicine,4 Inflammation and
Immunology Research Group,2 and Center
for Excellence in Arthritis and Rheumatism,5
Louisiana State University Health Sciences Center, Shreveport,
Louisiana 71130
Received 3 August 2000/Returned for modification 27 September
2000/Accepted 29 January 2001
 |
ABSTRACT |
Vascular endothelial integrity, assessed by Evans blue dye
extrusion and radiolabeled monoclonal antibody leakage, was markedly compromised in the brain, lung, kidney, and heart during
Plasmodium berghei infection, a well-recognized model for
human cerebral malaria. The results for vascular permeability from both
methods were significantly (P < 0.001) related.
| |
TEXT |
Changes in vascular permeability are
important in the pathogenesis of circulatory shock. Circulatory shock
is defined as an inadequacy of blood flow in tissue leading to
inadequate delivery of nutrients to tissue and inadequate removal of
waste products (reviewed in reference 12). Cardiac
abnormalities, such as myocardial infarction, heart arrhythmias, and
heart valve dysfunction, lead to circulatory shock. Diminished blood
volume, decreased vascular tone, or a blockage of blood flow in the
circulation all lead to circulatory shock. Of most interest to
infectious disease research is the development of circulatory shock
caused by infectious agents, also called septic shock. General features
of septic shock include vasodilation with changes in vascular
permeability, decreased mean arterial blood pressure, and disseminated
intravascular coagulation (12, 38), which are all
important factors contributing to decreased tissue perfusion
(12). In the late stages of septic shock, this coagulation
of blood (sometimes referred to as sludging blood) and other factors
leads to impaired consciousness (38). If the patient
recovers from septic shock, there is generally no neurological
impairment (38).
Malaria, a leading infectious cause of morbidity and mortality, is
postulated to cause an inflammatory response (3, 35). Petechial hemorrhaging into the brain is considered a hallmark of
cerebral malaria (CM), indicating the brain vasculature in patients
with Plasmodium falciparum malaria is often damaged
(25, 31). However, the exact contribution of vascular
leakage to human CM is still not defined because a recent study by
Brown et al. (2) did not detect significant vascular
leakage into brains of patients with severe P. falciparum
malaria. Patients with P. falciparum infections also develop
lung (respiratory distress syndrome), liver, and kidney damage
(18). The precise causes of vascular activation and damage
in humans are under intense debate, but it is difficult to define
pathogenic mechanisms in humans for obvious ethical reasons. Although
no model entirely replicates the human condition (reviewed in reference
8), two well-characterized models of CM exist (10,
22, 30, 32). We selected the P. berghei model because
P. berghei-infected mice develop impaired consciousness
(10, 22, 30). Susceptible mice (C57BL/6 or C3H) infected
with P. berghei develop neurological abnormalities 6 days
after injection with P. berghei (10, 22). These
mice exhibit brain edema, petechial hemorrhages, and monocyte infiltration (30). Several studies using dye extrusion
into tissue have documented that vascular permeability is markedly increased in the brain (21, 24, 26). In addition,
injection of P. berghei-infected mice with folic acid
results in convulsions, indicating that folic acid has crossed the
normally impermeable blood-brain barrier and is mediating altered brain
signaling (14). Ultrastructural analysis shows
perivascular edema in the brain after P. berghei infection
in mice (29). There is only a single semiquantitative
study of tissue damage outside the brain. Neill and Hunt report
extrusion of Monastral Blue, a colloidal dye, into brains, lungs,
livers, spleens, and kidneys of P. berghei ANKA-infected
mice, i.e., in all organs tested (27).
Because defining the sites of organ damage during malaria is key to our
understanding of pathogenic mechanisms, we quantified vascular
permeability during malaria in a number of tissues, using standard
Evans blue dye leakage. Since there are a number of disadvantages associated with the Evans blue dye leakage technique, we also assessed
vascular permeability using a radiolabeled monoclonal antibody (MAb)
technique and compared the results to those for Evans blue dye
extrusion. It is important to quantify precisely vascular leak in order
to define the mechanism(s) whereby damage to the endothelium occurs;
this ability to measure vascular permeability rapidly is important for
malarial research, septic shock, and other forms of circulatory shock.
We report here that the radiolabeled MAb technique correlated with
Evans blue dye extrusion. Moreover, we observed increased vascular
permeability during P. berghei infection in the brain, lung,
heart, and kidney, whereas no changes were detected in the small bowel,
large bowel, pancreas, liver and spleen.
Parasites and infection of mice.
Female (C57BL/6,
IL-120/0, GKO0/0, ICAM-10/0, and
TNFR10/0) mice all on the CM-susceptible C57BL/6 background
were purchased from Jackson Laboratory (Bar Harbor, Maine) at 4 to 5 weeks of age and provided food and water ad libitum. In each
experiment, groups of four to eight mice between 6 and 12 weeks of age
were used. The animals were housed at the Louisiana Health Sciences
Center Animal Care Facility, an Association for Assessment and
Accreditation of Laboratory Animal Care-approved facility.
IL-120/0, GKO0/0, ICAM-10/0, and
TNFR10/0 mice lack intact interleukin-12 (IL-12), gamma
interferon (IFN-
), intracellular adhesion molecule 1 (ICAM-1), and
tumor necrosis factor receptor 1 (TNFR1) genes, respectively (6,
23, 28, 33), and do not develop clinical signs and symptoms of CM.
P. bergehi ANKA, a gift from William Weidanz, was maintained
and used as described previously (15). This strain of
Plasmodium kills CM-susceptible C57BL/6 mice on about day 6 of infection. Frozen parasite stabilate was injected intraperitoneally
into a CM-resistant BALB/c source mouse. Blood was obtained from the source mouse to generate the inoculum for the experimental animals. Experimental mice were injected intraperitoneally with 106
erythrocytes parasitized with P. berghei, and parasitemia
was assessed by enumerating between 200 and 1,000 erythrocytes in Giemsa-stained thin blood films.
Assessment of vascular permeability.
Vascular permeability was
measured simultaneously by Evans blue dye extraction and by the
radiolabeled MAb technique. C57BL/6 mice were anesthetized by a
subcutaneous injection of 150 mg of ketamine and 7.5 mg of xylazine per
kg of body weight. The right jugular vein and right carotid artery were
cannulated with polyethylene tubing (PE-10); 200 µl of Evans blue in
saline (2%) was administered via the catheter in the jugular vein,
followed by an injection of 200 µl of 0.9% saline. The Evans blue
dye circulated for 11 min, and then 500,000 ± 100,000 cpm (0.5 to
5 mg in 200 µl) of nonbinding 131I anti-human P-selection
MAb was injected via the jugular vein catheter. No difference
(correlation coefficient [R2] = 0.08) in
permeability was measured in this range of specific activities. We used
a fixed specific activity for the nonbinding MAb because it allows the
simultaneous measurement of vascular permeability and cell adhesion
molecule expression. Cell adhesion molecule expression is determined as
the ratio of tissue accumulation of an 125I-labeled
specific MAb to the 131I-labeled nonspecific MAb
(1). The nonbinding anti-human P-selectin MAb (designated
P-23) was kindly provided by Donald Anderson (Pharmacia-Upjohn) and was
labeled by the Iodogen method (1). This antibody is characterized as nonbinding because in comparison to well-established binding MAbs, its accumulation in tissue was minimal and equivalent to
that of other nonspecific MAbs. Further, P-23 did not bind to
monolayers of cultured murine endothelial cells. Two hundred microliters of 0.9% saline containing 50 U of heparin was injected and
allowed to circulate for 5 min. A blood sample (200 µl) was then
obtained through the carotid artery to determine 131I
levels in serum. An isovolemic blood exchange with bicarbonate-buffered saline (6 ml) was performed through the jugular vein catheter. The
thoracic inferior vena cava was cut and flushed with 15 ml of
bicarbonate-buffered saline through the carotid artery catheter. Selected organs were dissected from the animal, weighed, and placed in
a test tube containing 1 ml of N,N-dimethyl
formamide. The levels of radioactivity were immediately assessed by a
scintillation counter (Wizard 3; Wallac, Turku, Finland). The level of
131I in tissue was divided by the weight of the tissue and
then divided by 131I per milliliter of plasma; the
131I per milliliter of plasma compensates for differences
in the concentration of radiolabel achieved in the sera of each animal, which is a factor in the permeability measurement. After determining the radioactivity level in each organ, the amount of Evans blue dye in
each organ was assessed by placing the organ in 1 ml of N,N-dimethyl formamide (Sigma, St. Louis, Mo.)
for 48 h to extract the Evans blue dye. The absorbance of Evans
blue dye solution was measured in a spectrophotometer at 630 nm. If the
absorbance was greater than 0.7 optical density units (OD), then the
solution was diluted with N,N-dimethyl formamide
until the absorbance fell below 0.7 OD. This dilution was necessary to
ensure measurements were made in the linear range of the
spectrophotometer. The absorbance value was divided by weight of tissue
to normalize for the amount of tissue. In other experiments, vascular
permeability was assessed only by the radiolabled MAb method, performed
as described above except that no Evans blue dye was injected.
Statistical analysis.
Analysis of variance with the Statview
program (SAS Institute, Cary, N.C.) was performed to statistically
compare Evans blue dye and radiolabeled MAb leakage in the different
groups of mice. Linear regression analysis of the results was also
performed with this program.
Results and discussion.
Evans blue dye when injected into
blood binds to serum proteins, with the majority binding to albumin. If
changes in vascular permeability occur, then dye leaks from vascular
lumen into interstitial tissue. The dye in the circulation is then
washed out, and the tissues can be visually inspected for dye leakage.
For brains and lungs, visualization of dye leakage is easy (data not
shown); for more pigmented organs, the dye is difficult to see in
tissue. Leakage of dye into the brain coincided with areas of petechial hemorrhaging. Little if any Evans blue dye was retained in the tissue
after fixation and paraffin embedding or after snap-freezing in liquid
nitrogen and fixation in acetone. We therefore used the technique of
Tateishi et al. (34) to extract and quantify dye in tissue.
In organs from uninfected mice, the amount of dye or radiolabel in the
tissue is proportional to the amount of vascularization
and the
permeability of the endothelial barrier. Thus, in the
brain, with a
tight endothelial barrier and less vascularization
than the lung, dye
extrusion is about 15-fold lower than in the
lung (Table
1). The spleen and liver, which are blood
filtration
organs with wide pores, have higher dye extrusion levels
than
the lung (Table
1).
On day 4 of
P. berghei infection, parasitemia of mice was
3.1% ± 4.2%, but these mice have no obvious clinical signs of
malaria.
On day 6 of infection, parasitemia was 13% ± 4%, and
virtually
all of these mice developed symptoms. The mice were
lethargic,
were breathing rapidly, and had obvious neurological
impairment,
such as loss of righting reflex and the ability to grip.
Mice
on day 4 of
P. berghei infection had markedly increased
vascular
permeability in the brain, lung, heart, and kidney as assessed
by the radiolabeled MAb technique or by Evans blue dye leakage
(Table
1). Changes in vascular permeability in the kidney may
be due to
increased glomerular filtration. The vascular permeability
increased
further on day 6 of
P. berghei infection in the brain,
lung,
heart, and kidney but not in the liver, spleen, and small
intestine. In
separate experiments, mice on day 2 of
P. berghei infection
had less than 0.1% parasitemia and similar levels of
vascular
permeability, assessed by Evans blue dye extrusion, as
uninfected
controls.
The brain showed the most pronounced change in vascular permeability
during
P. berghei malaria when assessed by the radiolabeled
MAb technique, increasing more than 10-fold compared with uninfected
controls (Table
1). The lung, heart, and kidney also showed significant
(
P < 0.05) increases in vascular permeability,
generally about
threefold. This increase in vascular leak occurred on
day 4 of
infection when the mice were asymptomatic, indicating that the
observed vascular leakage did not occur merely because the animal
was
moribund. Additional Evans blue and radiolabeled MAb experiments
showed
variation from experiment to experiment in the magnitude
of
permeability changes in the lung and brain. In every experiment
changes
in the lung and brain reached statistical significance,
but in some
experiments changes in vascular permeability were
greater in the lung
than in the brain, whereas other experiments
showed more pronounced
changes in the brain. The reason for these
differences remains to be
determined. The permeability in liver
and intestine did not increase
markedly during the course of
P. berghei malaria. The spleen
showed a decline in vascular leakage,
which was not statistically
significant. The decline in permeability
may be due to development of
shunts in the spleen between the
arterioles and venules reducing
perfusion through the spleen (
36);
alternatively, it may
be due to the hepatomegaly and splenomegaly
that occur during malaria.
However, it is difficult to interpret
changes in permeability in the
liver and spleen because these
organs are blood filtration organs and
as such have wide pores
allowing passage of large macromolecules and
cells.
The results for vascular permeability were similar for Evans blue dye
leakage and the radiolabeled MAb technique. Indeed,
there was a
significant (
P < 0.001) correlation in the lung,
heart,
liver, spleen, small bowel, kidneys, pancreas, and brain between
the vascular permeability measured by Evans blue dye leakage and
that
assessed by radiolabel leakage. The
R2 values
ranged from 0.50 in the liver to 0.91 in the spleen (Table
1); the
pancreas and large bowel
R2 values were 0.56 and
0.82, respectively. For correlation of the
Evans blue dye leakage and
radiolabeled MAb techniques, changes
in vascular permeability must
occur. In those tissues where we
observed increased vascular
permeability during the course of
P. berghei malaria, we
also observed excellent linear correlation
(high
R2) between the two techniques (Table
1). In the
liver, we detect
little if any change in permeability by the Evans blue
dye technique
and the lowest
R2 (Table
1). The
spleen appears to be the exception, with a high
R2 but no significant change in vascular
permeability. However,
changes did occur during malaria that may
explain the excellent
correlation between the two methods for measuring
vascular permeability
(Table
1). Collectively, these results indicate
that the radiolabel
MAb technique is equivalent to the Evans blue dye
technique.
Assessing vascular permeability is much more rapid and straightforward
by the radiolabeled MAb technique than by the Evans
blue dye method.
The latter requires a 48-h extraction of the
dye from tissue and then
measurement of the absorbance in a spectrophotometer.
The solution
containing the extracted dye is added manually to
a cuvette, which is
placed in the spectrophotometer. A measurement
is made, the cuvette is
rinsed, and another sample is added; this
is a slow process. In
addition, many tissue samples, especially
after induction of increased
permeability, require dilution to
bring the absorbance into the linear
range. Collectively, these
manual steps make determination of vascular
permeability by Evans
blue dye leakage into tissue a time-consuming
process and explain
why few tissues are generally assessed by this
technique (Tables
1 and
2). In contrast,
with the radiolabeled MAb technique,
the tissue dissected from an
animal is placed in scintillation
fluid, and the amount of
radioactivity present is assessed on
a scintillation counter. No
dilutions or further processing are
required, and the scintillation
counter automatically measures
the radioactivity in each vial. Another
advantage of this technique
over Evans blue dye leakage is that it
takes into account the
driving force behind permeability, namely, the
concentration of
radiolabel achieved in the blood.
View this table:
[in this window]
[in a new window]
|
TABLE 2.
Vascular permeability assessed by radiolabeled MAb
leakage into additional tissues during the course of P. berghei malaria
|
|
Several studies have determined that the blood-brain barrier is
compromised during
P. berghei malaria. A single study using
a colloidal Monastral Blue reports that there is increased permeability
in the kidneys livers lungs, spleens, and brains of
P. berghei-infected
mice (
27). This approach entails
examining tissue sections from
Monastral Blue-treated mice and visually
scoring the amount of
leakage. The advantage of Monastral Blue is that
direct visualization
of dye extrusion into tissue is obtained; the
disadvantages are
that the measurements are subjective and
time-consuming. In addition,
there is no correlation between the
location of petechial hemorrhages
in the brain and localization of
Monastral Blue particles. How
the vascular endothelium retained
Monastral Blue while allowing
an erythrocyte to cross was not
addressed. The results of Neill
and Hunt (
27) raise the
possibility that Monastral Blue particles
are transported across the
endothelium analogously to the transport
of latex beads across mucosal
epithelium. In our experiments,
we found colocalization of Evans blue
dye leakage and petechial
hemorrhages on the surface of brains from
P. berghei-infected
mice (data not shown). With both Evans
blue dye leakage and the
radiolabeled MAb technique, we found markedly
increased vascular
permeability in the brain, lung, and kidney, which
corroborates
the results of Neill and Hunt (
27). Our study
extends their
finding to myocardial tissue. We did not observe an
increase in
vascular permeability for the spleen and liver as reported
by
Neill and Hunt (
27); this difference may be due to the
size
of Monastral Blue particles and their active transport across
the
endothelium as described
above.
Having established that the radiolabeled MAb technique measures
vascular permeability, we applied it to induced mutant mice
that are
protected from CM to determine whether these mice are
protected from
increased vascular permeability. ICAM-1-, IL-12-,
TNFR1-, and
IFN-
-deficient mice do not develop and succumb to
CM after infection
with
P. berghei (
7,
9,
11,
20). All
strains of
mice had significant parasitemia (Table
3). Thus,
changes in vascular
permeability cannot be attributed to inadequate
infection. The
parasitemia after injection of 10
6 P. berghei-parasitized erythrocytes was markedly enhanced in
IL-12-
and IFN-
-deficient mice compared with C57BL/6 controls,
with the
caveat that the groups of mice were not injected with
the same inoculum
of parasites. Each type of mouse developed significantly
(
P < 0.05) increased vascular permeability in the brain and lung
during
P. berghei malaria compared with uninfected matched
controls
(Table
4). Significantly
(
P < 0.05) increased permeability during
P. berghei malaria in the heart was detected in TNFR1-deficient
mice
and C57BL/6 controls. Decreased or similar permeability was
observed in
spleens and livers of
P. berghei-infected mice compared
with
uninfected controls for each type of mouse. These results
collectively
indicate that vascular permeability changes during
P. berghei malaria occur in a number of tissues, but these changes
by
themselves are not life threatening or are markedly ameliorated
by
damping the inflammatory response. A change in vascular permeability
is
probably one factor of many that ultimately leads to death
from
malaria.
View this table:
[in this window]
[in a new window]
|
TABLE 3.
Parasitemia in selected induced mutant mice (five to
eight mice per group) on days 4 and 6 of P. berghei
infection
|
|
View this table:
[in this window]
[in a new window]
|
TABLE 4.
Vascular permeability assessed by radiolabeled MAb
leakage in tissues of selected induced mutant mice on day 6 of
P. berghei malaria
|
|
Vascular permeability is a major factor in the pathogenesis of
circulatory shock, and our results show that the radiolabeled
MAb
technique is a useful assay to measure vascular permeability
changes.
Our finding of significant vascular leakage in several
tissues
(including pancreas and thymus) during the course of
P. berghei malaria raises the question of whether circulatory shock
may explain the pathogenesis of malaria. Individuals in septic
shock
and those with CM both develop impaired consciousness, and
only very
few individuals in septic shock or with CM develop neurological
sequelae if they recover, suggesting similar pathogenic mechanisms
in
the brain. In addition, individuals with septic shock often
have
sludging blood wherein minithrombi are formed. This may be
analogous to
the rosetting described in CM with parasitized and
nonparasitized
erythrocytes binding together, although the precise
role of rosetting
in CM is under debate (
25). Jennings et al.
(
16,
17) have proposed that CM is an encephalitis or inflammation
of
the brain. Indeed, immune cells (macrophages; CD4
+ and
CD8
+ T cells) and inflammatory cytokines are essential for
the pathogenesis
of experimental CM (
4,
5,
13,
19,
37).
When extrapolated
to other tissues showing vascular damage, these
results suggest
that CM is a systemic inflammatory
response.
Our results showing damage during experimental malaria in the brain,
lung, heart, and kidney may be important because vascular
damage is
also reported in these tissues in humans infected with
P. falciparum. Humans with
P. falciparum malaria succumb
to CM,
respiratory distress, anemia, and occasionally acute kidney
failure.
These life-threatening complications often occur in the same
patient
with
P. falciparum malaria. The results of others
and our studies
show compromised vascular permeability in the brain;
this compromise
may contribute to the pathogenesis of experimental CM.
Whether
this compromise in brain vascular integrity occurs during human
CM is controversial (
2). Our observation of increased
vascular
leak in kidneys suggests that kidneys may also be damaged
during
experimental malaria. The finding of an early compromise of the
blood-lung barrier during
P. berghei malaria prior to the
onset
of symptoms suggests that these animals develop lung injury at
an
early stage. Damage to the heart during
P. berghei malaria
may lead to cardiac insufficiency and might further exacerbate
the
respiratory distress syndrome. The fact that all of these
pathologic
changes occur in the same animal suggests that the
mechanisms mediating
damage may be similar. Collectively, these
observations suggest that
experimental malaria may yield important
information regarding human
malarial
pathogenesis.
| |
ACKNOWLEDGMENTS |
This research was supported by NIH grants KO8 AI01438, PO1 DK43785,
and RO1 AI40667. Support was also received from the Center for
Excellence in Arthritis and Rheumatism.
We acknowledge the assistance of Clay Watson, Deborah Yanez, Dean
Manning, and William Weidanz in initiating these studies.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: LSU Health
Sciences Center
Shreveport, Department of Microbiology and Immunology,
P.O. Box 33932, Shreveport, LA 71130. Phone: (318) 675-4457. Fax: (318) 675-5764. E-mail: hvande{at}lsuhsc.edu.
Editor:
J. M. Mansfield
| |
REFERENCES |
| 1.
|
Bauer, P.,
C. W. Lush,
P. R. Kvietys,
J. M. Russell, and D. N. Granger.
2000.
Role of endotoxin in the expression of endothelial selectins after cecal ligation and perforation.
Am. J. Physiol
278:R1140-R1147[Abstract/Free Full Text].
|
| 2.
|
Brown, H. C.,
T. T. Chau,
N. T. Mai,
N. P. Day,
D. X. Sinh,
N. J. White,
T. T. Hien,
J. Farrar, and G. D. Turner.
2000.
Blood-brain barrier function in cerebral malaria and CNS infections in Vietnam.
Neurology
55:104-111[Abstract/Free Full Text].
|
| 3.
|
Clark, I. A., and K. A. Rockett.
1995.
TNF, malaria, and sepsis.
Lancet
345:929[Medline].
|
| 4.
|
Curfs, J. H.,
C. C. Hermsen,
P. Kremsner,
S. Neifer,
J. H. Meuwissen,
N. Van Rooyen, and W. M. Eling.
1993.
Tumour necrosis factor-alpha and macrophages in Plasmodium berghei-induced cerebral malaria.
Parasitology
107:125-134.
|
| 5.
|
Curfs, J. H.,
P. H. van der Meide,
A. Billiau,
J. H. Meuwissen, and W. M. Eling.
1993.
Plasmodium berghei: recombinant interferon-gamma and the development of parasitemia and cerebral lesions in malaria-infected mice.
Exp. Parasitol.
77:212-223[CrossRef][Medline].
|
| 6.
|
Dalton, D. K.,
S. Pitts-Meek,
S. Keshav,
I. S. Figari,
A. Bradley, and T. A. Stewart.
1993.
Multiple defects of immune cell function in mice with disrupted interferon-gamma genes.
Science
259:1739-1742[Abstract/Free Full Text].
|
| 7.
|
de Kossodo, S., and G. E. Grau.
1993.
Role of cytokines and adhesion molecules in malaria immunopathology.
Stem Cells
11:41-48[Medline].
|
| 8.
|
Eling, W. M., and P. G. Kremsner.
1994.
Cytokines in malaria, pathology and protection.
Biotherapy
7:211-221[CrossRef][Medline].
|
| 9.
|
Favre, N.,
C. Da Laperousaz,
B. Ryffel,
N. A. Weiss,
B. A. Imhof,
W. Rudin,
R. Lucas, and P. F. Piguet.
1999.
Role of ICAM-1 (CD54) in the development of murine cerebral malaria.
Microbes Infect.
1:961-968[CrossRef][Medline].
|
| 10.
|
Finley, R. W.,
L. J. Mackey, and P. H. Lambert.
1982.
Virulent P. berghei malaria: prolonged survival and decreased cerebral pathology in cell-dependent nude mice.
J. Immunol.
129:2213-2218[Abstract].
|
| 11.
|
Grau, G. E.,
H. Heremans,
P. F. Piguet,
P. Pointaire,
P. H. Lambert,
A. Billiau, and P. Vassalli.
1989.
Monoclonal antibody against interferon gamma can prevent experimental cerebral malaria and its associated overproduction of tumor necrosis factor.
Proc. Natl. Acad. Sci. USA
86:5572-5574[Abstract/Free Full Text].
|
| 12.
|
Guyton, A. C., and J. E. Hall.
1996.
Circulatory shock and physiology of its treatment, p. 285-293.
In
A. C. Guyton, and J. E. Hall (ed.), Textbook of medical physiology. The W. B. Saunders Company, Philadelphia, Pa.
|
| 13.
|
Hermsen, C.,
T. van de Wiel,
E. Mommers,
R. Sauerwein, and W. Eling.
1997.
Depletion of CD4+ or CD8+ T-cells prevents Plasmodium berghei induced cerebral malaria in end-stage disease.
Parasitology
114:7-12.
|
| 14.
|
Hermsen, C. C.,
E. Mommers,
T. van de Wiel,
R. W. Sauerwein, and W. M. Eling.
1998.
Convulsions due to increased permeability of the blood-brain barrier in experimental cerebral malaria can be prevented by splenectomy or anti-T cell treatment.
J. Infect. Dis.
178:1225-1227[Medline].
|
| 15.
|
Hoffmann, E. J.,
W. P. Weidanz, and C. A. Long.
1984.
Susceptibility of CXB recombinant inbred mice to murine plasmodia.
Infect. Immun.
43:981-985[Abstract/Free Full Text].
|
| 16.
|
Jennings, V. M.,
J. K. Actor,
A. A. Lal, and R. L. Hunter.
1997.
Cytokine profile suggesting that murine cerebral malaria is an encephalitis.
Infect. Immun.
65:4883-4887[Abstract].
|
| 17.
|
Jennings, V. M.,
A. A. Lal, and R. L. Hunter.
1998.
Evidence for multiple pathologic and protective mechanisms of murine cerebral malaria.
Infect. Immun.
66:5972-5979[Abstract/Free Full Text].
|
| 18.
|
Kampfl, A.,
B. Pfausler,
H. P. Haring,
D. Denchev,
E. Donnemiller, and E. Schmutzhard.
1997.
Impaired microcirculation and tissue oxygenation in human cerebral malaria: a single photon emission computed tomography and near-infrared spectroscopy study.
Am. J. Trop. Med. Hyg.
56:585-587.
|
| 19.
|
Lucas, R.,
J. Lou,
D. R. Morel,
B. Ricou,
P. M. Suter, and G. E. Grau.
1997.
TNF receptors in the microvascular pathology of acute respiratory distress syndrome and cerebral malaria.
J. Leukoc. Biol.
61:551-558[Abstract].
|
| 20.
|
Lucas, R.,
J. N. Lou,
P. Juillard,
M. Moore,
H. Bluethmann, and G. E. Grau.
1997.
Respective role of TNF receptors in the development of experimental cerebral malaria.
J. Neuroimmunol.
72:143-148[CrossRef][Medline].
|
| 21.
|
Ma, N.,
N. H. Hunt,
M. C. Madigan, and T. Chan-Ling.
1996.
Correlation between enhanced vascular permeability, up-regulation of cellular adhesion molecules and monocyte adhesion to the endothelium in the retina during the development of fatal murine cerebral malaria.
Am. J. Pathol.
149:1745-1762[Abstract].
|
| 22.
|
Mackey, L. J.,
A. Hochmann,
C. H. June,
C. E. Contreras, and P. H. Lambert.
1980.
Immunopathological aspects of Plasmodium berghei infection in five strains of mice. II. Immunopathology of cerebral and other tissue lesions during the infection.
Clin. Exp. Immunol.
42:412-420[Medline].
|
| 23.
|
Magram, J.,
S. E. Connaughton,
R. R. Warrier,
D. M. Carvajal,
C. Y. Wu,
J. Ferrante,
C. Stewart,
U. Sarmiento,
D. A. Faherty, and M. K. Gately.
1996.
IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses.
Immunity
4:471-481[CrossRef][Medline].
|
| 24.
|
Medana, I. M.,
T. Chan-Ling, and N. H. Hunt.
2000.
Reactive changes of retinal microglia during fatal murine cerebral malaria: effects of dexamethasone and experimental permeabilization of the blood-brain barrier.
Am. J. Pathol.
156:1055-1065[Abstract/Free Full Text].
|
| 25.
|
Miller, L. H.,
M. F. Good, and G. Milon.
1994.
Malaria pathogenesis.
Science
264:1878-1883[Abstract/Free Full Text].
|
| 26.
|
Neill, A. L.,
T. Chan-Ling, and N. H. Hunt.
1993.
Comparisons between microvascular changes in cerebral and non-cerebral malaria in mice, using the retinal whole-mount technique.
Parasitology
107:477-487.
|
| 27.
|
Neill, A. L., and N. H. Hunt.
1992.
Pathology of fatal and resolving Plasmodium berghei cerebral malaria in mice.
Parasitology
105:165-175.
|
| 28.
|
Pfeffer, K.,
T. Matsuyama,
T. M. Kundig,
A. Wakeham,
K. Kishihara,
A. Shahinian,
K. Wiegmann,
P. S. Ohashi,
M. Kronke, and T. W. Mak.
1993.
Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection.
Cell
73:457-467[CrossRef][Medline].
|
| 29.
|
Polder, T. W.,
W. M. Eling,
J. H. Curfs,
C. R. Jerusalem, and M. Wijers-Rouw.
1992.
Ultrastructural changes in the blood-brain barrier of mice infected with Plasmodium berghei.
Acta Leiden
60:31-46[Medline].
|
| 30.
|
Rest, J. R.
1982.
Cerebral malaria in inbred mice. I. A new model and its pathology.
Trans. R. Soc. Trop. Med. Hyg.
76:410-415[CrossRef][Medline].
|
| 31.
|
Riganti, M.,
E. Pongponratn,
T. Tegoshi,
S. Looareesuwan,
B. Punpoowong, and M. Aikawa.
1990.
Human cerebral malaria in Thailand: a clinico-pathological correlation.
Immunol. Lett.
25:199-205[CrossRef][Medline].
|
| 32.
|
Shear, H. L.,
M. W. Marino,
C. Wanidworanun,
J. W. Berman, and R. L. Nagel.
1998.
Correlation of increased expression of intercellular adhesion molecule-1, but not high levels of tumor necrosis factor-alpha, with lethality of Plasmodium yoelii 17XL, a rodent model of cerebral malaria.
Am. J. Trop. Med. Hyg.
59:852-858[Abstract].
|
| 33.
|
Sligh, J. E., Jr.,
C. M. Ballantyne,
S. S. Rich,
H. K. Hawkins,
C. W. Smith,
A. Bradley, and A. L. Beaudet.
1993.
Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1.
Proc. Natl. Acad. Sci. USA
90:8529-8533[Abstract/Free Full Text].
|
| 34.
|
Tateishi, H.,
K. Mitsuyama,
A. Toyonaga,
M. Tomoyose, and K. Tanikawa.
1997.
Role of cytokines in experimental colitis: relation to intestinal permeability.
Digestion
58:271-281[Medline].
|
| 35.
|
Usawattanakul, W.,
S. Tharavanij,
D. A. Warrell,
S. Looareesuwan,
N. J. White,
S. Supavej, and S. Soikratoke.
1985.
Factors contributing to the development of cerebral malaria. II. Endotoxin.
Clin. Exp. Immunol.
61:562-568[Medline].
|
| 36.
|
Weiss, L.,
U. Geduldig, and W. Weidanz.
1986.
Mechanisms of splenic control of murine malaria: reticular cell activation and the development of a blood-spleen barrier.
Am. J. Anat.
176:251-285[CrossRef][Medline].
|
| 37.
|
Yanez, D. M.,
D. D. Manning,
A. J. Cooley,
W. P. Weidanz, and H. C. van der Heyde.
1996.
Participation of lymphocyte subpopulations in the pathogenesis of experimental murine cerebral malaria.
J. Immunol.
157:1620-1624[Abstract].
|
| 38.
|
Young, L. S.
2000.
Sepsis syndrome, p. 806-820.
In
G. L. Mandel, J. E. Bennett, and R. Dolin (ed.), Principles and practice of infectious diseases. Churchill Livingstone, Philadelphia, Pa.
|
Infection and Immunity, May 2001, p. 3460-3465, Vol. 69, No. 5
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.5.3460-3465.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Penet, M.-F., Abou-Hamdan, M., Coltel, N., Cornille, E., Grau, G. E., de Reggi, M., Gharib, B.
(2008). Protection against cerebral malaria by the low-molecular-weight thiol pantethine. Proc. Natl. Acad. Sci. USA
105: 1321-1326
[Abstract]
[Full Text]
-
Wu, M. H.
(2005). Endothelial focal adhesions and barrier function. J. Physiol.
569: 359-366
[Abstract]
[Full Text]
-
Levy, B., Vallee, C., Lauzier, F., Plante, G. E., Mansart, A., Mallie, J.-P., Lesur, O.
(2004). Comparative effects of vasopressin, norepinephrine, and L-canavanine, a selective inhibitor of inducible nitric oxide synthase, in endotoxic shock. Am. J. Physiol. Heart Circ. Physiol.
287: H209-H215
[Abstract]
[Full Text]
-
Sun, G., Chang, W.-L., Li, J., Berney, S. M., Kimpel, D., van der Heyde, H. C.
(2003). Inhibition of Platelet Adherence to Brain Microvasculature Protects against Severe Plasmodium berghei Malaria. Infect. Immun.
71: 6553-6561
[Abstract]
[Full Text]
-
Dodd-o, J. M., Hristopoulos, M. L., Faraday, N., Pearse, D. B.
(2003). Effect of ischemia and reperfusion without airway occlusion on vascular barrier function in the in vivo mouse lung. J. Appl. Physiol.
95: 1971-1978
[Abstract]
[Full Text]
-
Chang, W.-L., Jones, S. P., Lefer, D. J., Welbourne, T., Sun, G., Yin, L., Suzuki, H., Huang, J., Granger, D. N., van der Heyde, H. C.
(2001). CD8+-T-Cell Depletion Ameliorates Circulatory Shock in Plasmodium berghei-Infected Mice. Infect. Immun.
69: 7341-7348
[Abstract]
[Full Text]
Top
Abstract
Text
