(Chest. 2001;120:1301-1308.)
© 2001
American College of Chest Physicians
Initial Evidence of Endothelial Cell Apoptosis as a Mechanism of Systemic Capillary Leak Syndrome*
Ragheb Assaly, MD;
Dan Olson, MD, PhD, FCCP;
Jeffrey Hammersley, MD, FCCP;
Pan-Sheng Fan, MD;
Jiang Liu, PhD;
Joseph I. Shapiro, MD and
M. Bashar Kahaleh, MD
*
From the Departments of Medicine and Pharmacology, Medical College of Ohio, Toledo, OH.
Correspondence to: M. Bashar Kahaleh, MD, Professor of Medicine and Chief, Division of Rheumatology, Department of Medicine, Medical College of Ohio, 3000 Arlington Ave, Toledo, OH 43614; e-mail: bkahaleh{at}mco.edu
 |
Abstract
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Background: Systemic capillary leak syndrome (SCLS) is
a rare disorder of unknown etiology that is characterized by acute
recurrent attacks of hypovolemic shock commonly following an
inflammatory stimulus such as a viral illness. Prophylactic therapy is
generally ineffective, and the outcome is frequently fatal.
Methods: In order to investigate the cellular mechanisms
leading to SCLS, we examined the effects of sera from two patients with
active SCLS on microvascular endothelial cell apoptosis in
vitro. Apoptosis was determined by morphologic criteria, DNA
fragmentation, annexin V stain, and by a quantitative photometric
assay. The apoptotic pathway was investigated by Western blot of
endothelial cells lysate after exposure to SCLS sera.
Results: The sera from patients with active SCLS mediated
profound apoptosis of microvascular endothelial cells shortly after
exposure. The exposed microvascular endothelial cells underwent
immediate apoptosis as evidenced by morphologic changes, plasma
membrane phosphatidylserine exposure, and by DNA fragmentation.
Increased Bax/Bcl-2 ratio in endothelial cells exposed to SCLS sera was
observed and suggested an oxidation injury as the possible mechanism
for endothelial apoptosis. This potential mechanism was further
explored by measuring intracellular reactive oxygen species (ROS)
following SCLS serum exposure. Sera from both patients caused marked
increases in ROS, initially detectable at 1 h and persisted for at
least 12 h, with control serum from healthy subjects showing no
effect on basal endothelial cell ROS concentrations.
Conclusion: Components from the sera of patients with
active systemic capillary leak syndrome in contrast to healthy subject
sera mediate early and extensive endothelial apoptosis in
vitro that is associated with oxidation injury. These data
represent compelling initial evidence for oxidation-induced apoptosis
as a likely mechanism for endothelial injury leading to
SCLS.
Key Words: apoptosis • capillary leak • endothelial cell
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Introduction
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Systemic
capillary leak syndrome (SCLS) is a rare disorder of unknown etiology
that is most common between the third and fifth decade of life. Both
sexes are equally affected. Clarkson et al1
described the
first case in 1960, and < 50 patients have been described since
then.2
The frequency of reports has increased in the last
5 years, reflecting more clinical awareness of the syndrome; this
suggests that the true incidence of SCLS may have been underestimated
in the past. SCLS is characterized by recurrent attacks of hypovolemia
and associated hypotension, hemoconcentration, generalized edema, and
in most cases, the presence of a paraprotein. The clinical signs during
attacks result from massive extravasation of large volume of plasma and
its constituents into the extracellular space. Death during the acute
attack from cardiopulmonary collapse occurs in approximately one third
of the cases.2
In the current study, we examine two
patients with well-defined SCLS, and we describe the induction of
endothelial apoptosis by SCLS sera to propose a potential mechanism for
the pathogenesis of this rare but fatal disease.
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Case Presentations
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Case 1
A 32-year-old African-American woman presented with a 3-day
history of flu-like symptoms. She was in acute distress with
hypotension (BP, 50/30 mm Hg), hypothermia (temperature, 34°C),
tachycardia (heart rate, 150 beats/min), and tachypnea (respiratory
rate, 27 breaths/min). Laboratory findings included the following:
hemoconcentration with hemoglobin, 20.8 g/dL; hematocrit, 61.6%; and
reduced bicarbonate, 13 mEq/L. Chest radiographic findings were normal,
and the ECG showed sinus tachycardia with right-axis deviation. Due to
the concern that sepsis was present, antibiotics were administered
after culture specimens were obtained. Fluid management dominated her
course over the next 22 h, and she received 15 L of normal saline
solution plus vasopressors to maintain BP at 80/60 mm Hg. Arterial
blood gas analysis on 2 L of O2 showed severe
metabolic acidosis with a pH of 7.12;
PCO2, 18 mm Hg;
PO2, 133 mg/Hg; and oxygen
saturation, 96%. Due to her severe ventilatory demand, she required
mechanical ventilation. Subsequent laboratory test results showed
elevated WBC count, 35,300/µL; hematocrit, 57.2%; and albumin
reduced to 1.1 g/dL. Cardiac index was 2.1 L/m2,
systemic vascular resistance was 1,732 dyne/U, and pulmonary vascular
resistance (PVR) was elevated to 304 dyne/U. On the third hospital day,
hemodynamic stability was achieved with BP of 90/60 mm Hg and
successful weaning of pressor therapy. On the fifth day, the hematocrit
stabilized at 28 to 30% and the albumin level rose to 2.9 g/dL.
Pertinent negative determinations included normal or negative serum
cortisol, toxicology screen, protein electrophoresis, viral studies,
blood cultures x 4, complement studies, and
C1-esterase levels. Immunoelectrophoresis showed
an IgG 
monoclonal protein spike (10 g/L), while bone marrow
findings were negative for multiple myeloma. She was successfully
weaned from mechanical ventilation on day 7 and discharged home after
13 days of hospitalization. One year later, the patient was
asymptomatic, BP was normal at 110/60 mm Hg, and the ECG returned to
normal. The diagnosis of SCLS in this case was made based on the
presence of the serum monoclonal paraprotein and the characteristic
clinical presentations in this 32-year-old woman with acute hypovolemia
and hemoconcentration.
Case 2
A 40-year-old white man presented with hypothermia (temperature,
36.2°C) and hypotension (BP, 60 mm Hg/inaudible) following a 2-day
history of flu-like illness. He subsequently developed diffuse
abdominal pain and a 10-lb weight gain. His medical history was
significant for three similar attacks in the previous year. Despite
severe hypotension, the patient was alert and oriented. General
physical examination findings were unremarkable, and laboratory
findings included leukocytosis (WBC count, 43,000/µL) and
hemoconcentration (hemoglobin 20, g/dL; hematocrit, 59.2%). Chest
radiographic findings were normal, but the ECG showed sinus tachycardia
at 124/min and acute right-axis deviation. This right-axis deviation
was present on an old ECG during a similar episode, but was not present
between attacks. Right and left cardiac catheterization and abdominal
CT failed to detect any abnormalities. With septic shock remaining the
most probable diagnosis, an exploratory laparotomy and cholecystectomy
were performed. However, no evidence of infection was found. Despite
all efforts, the patient’s condition continued to deteriorate, and the
patient died within 48 h of hospital admission. Postmortem
findings were significant for ascites, pleural and pericardial
effusions, hepatosplenic congestion, and elevated serum IgG with
normal bone marrow. With no other abnormality identified, the diagnosis
of SCLS was made
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Materials and Methods
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Patient Sera
Diseased sera (SCLS [n = 2; cases 1 and 2], sepsis
[n = 4], pancreatitis [n = 1]) and healthy sera (age-matched
donors [n = 6]) were collected and studied after approval of the
Internal Review Board at the Medical College of Ohio. Serum samples
were obtained from patient 1 at the onset, during, and at the end of
the acute disease, while only one serum sample was available from
patient 2. Also studied was an SCLS sample from patient 1 saved from a
prior hospital admission. The in vitro endothelial cell
exposure studies were always done using 10% serum concentrations.
Small variations in technique and duration of exposure as dictated by
the specific measurement are described for each of the tests in the
section on "Material and Methods."
Endothelial Cells
Normal dermal microvascular endothelial cells (Clonetics
Corporation; San Diego, CA) were cultured in endothelial growth medium
in 2% fetal bovine serum and used in the four-sixth passage. For
morphologic examination, the cells were grown in 36-mm plates and
observed with an inverted microscope. Disease and control sera were
added to cell cultures at 10% concentration for variable duration, as
noted in each method.
Analysis of DNA Fragmentation
Endothelial cells (3 x 106) were
harvested 24 h after serum exposure, washed twice in
phosphate-buffered saline solution, resuspended in 1 mL lysis buffer (3
mM ethylenediaminetetra-acetic acid, 10 mM Tris, 100 mM NaCl, 0.5%
Triton X-100) and incubated for 20 min on ice. The lysates were
centrifuged at 27,000g at 4°C for 20 min. DNA was
extracted from the supernatant with equal volumes of phenol followed by
chloroform and precipitated overnight at - 85°C in absolute ethanol
containing 0.3 mol/L sodium acetate. Samples were treated with
ribonuclease (200 µg/mL) for 10 min at 37°C followed by 5
min at 65°C, and nucleic acids were quantified by measuring
absorbance at 260 nm. Samples (20 µg) were separated by gel
electrophoresis (1.8% agarose gel for 3 h) and visualized under
ultraviolet illumination after staining with ethidium
bromide.3
Annexin V Stain
Annexin stain was performed using the ApoAlert kit according to
recommendations of the manufacturer (Clonetech; Palo Alto, CA).
Briefly, microvascular endothelial cells grown on cover slips in 10%
disease or control sera for 6 h were washed in annexin-binding
buffer and incubated with 1 µg/mL annexin V-fluorescein
isothiocyanate in the dark. Cells were visualized after washing using a
florescence microscope set at a dual fluorescein
isothiocyanate/rhodamine filters (Zeiss Institute; Zurich,
Switzerland).4
Quantitative Annexin V Binding Assay
An annexin V-enhanced green fluorescent protein kit was used
according to recommendations of the manufacturer (Clonetech). Briefly,
microvascular endothelial cells in 96-well Dyna Tech plates with black
opaque wells were cultured with control or patients sera at 10%
concentration for 6 h and washed with binding buffer and incubated
with 1 µg/mL annexin V-enhanced green fluorescent protein for 15 min.
Binding was read on plate fluorometer (excitation 485/20 and emission
508/20).5
Western Blot
Preparation of Cell Lysates:
Confluent microvascular
endothelial cell cultures were washed with cold Tris salt albumin
solution (0.002 mol/L Tris-Cl, pH 8.0, 0.14 M NaCl and 0.025%)
followed by addition of lysis buffer (Tris salt albumin solution with
2% Triton X-100, 5 mM iodoacetamide and proteinase inhibitors). The
cell lysate was then centrifuged for 10 min at 300g to
remove the nuclei, and the supernatant was centrifuged for 1 additional
h at 100,000g.
Polyacrylamide Gel and Western Blot:
The resulting
supernatant was separated on 10% polyacrylamide gel followed by
transfer of proteins from the gel to nitrocellulose membrane by semidry
transfer cell at 15 V for 20 min. The membrane was washed with Tris
buffered saline Tween (10 mM Tris-HCl, pH 8.0, 150 mM NaCl, 0.05%
Tween) and blocked with Tris buffered saline Tween and 5%
nonfat milk for 30 min. The membrane was incubated with primary
antibody at 1:1,000 dilution followed by an appropriate second antibody
conjugated with alkaline phosphatase followed by the addition of
5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium substrate
to detect the color reaction. Antibodies to Bax, Bcl-2, Bad, Fadd, Fas,
and Fas ligand (StressGen Corporation; British Columbia, Canada) were
used to probe the apoptosis pathway in endothelial
cells.6
7
Measurement of Intracellular Reactive Oxygen Species
To measure intracellular reactive oxygen species (ROS), we used
the fluorescent dye 2'-1' dichlorodihydrofluorescein diacetate,
which exhibits fluorescence at 520 nm when excited at 490 nm after
interaction with H2O2 or
O2 in a similar fashion to which we have
published previously.8
Intracellular ROS mediate the
linkage of Na+/K+-adenosine triphosphatase to hypertrophy and
its marker genes in cardiac myocytes. Endothelial cells were exposed to
control or patient serum for either 1 h or 12 h and then
loaded with 10 µM 5-6 chloromethyl-2'-7' dichlorodihydrofluorescein
diacetate for 15 min at 37C in the dark. Cells were then washed with
media several times and examined using a Ratioarc fluorometric imaging
system (Attofluor Instruments; Bethesda MD) interfaced with a Zeiss
inverted fluorescence microscope (Zeiss Instruments). The operator
examined several fields of cells at 40 x magnification using light
microscopy on which voxels were chosen to fit within each of the
visible cells. This field was then studied using the fluorescence
parameters described above and data recorded. All fields of cells were
studied using the same camera and computer settings, and fluorescence
values are reported as arbitrary units with 0 corresponding to no
signal and 256 representing the highest value. With these parameters,
cells that were not exposed to either control or experimental serum
samples exhibited fluorescence values of 76 ± 20 (mean ± SD;
n = 150 cells).
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Results
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Early and profound endothelial apoptosis was noted following cell
exposure to SCLS sera. Morphologic changes (shrinking and condensation)
were seen 4 h after SCLS serum exposure. Cellular apoptosis was
suggested by the morphologic appearance of the cells (Fig 1
) and was confirmed by DNA fragmentation (Fig 2 ) and by the annexin-V stain (Fig 3
).
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Figure 1.. Morphologic appearance of normal
(top, A) and apoptotic
(bottom, B) endothelial cells. Apoptotic
cells appear shrunken with condensed cytoplasm, nuclear fragmentation,
and extensive cell surface protrusion (original x 40).
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Figure 2.. Agarose gel electrophoresis of DNA isolated from
endothelial cells treated with control sera (left,
A) and SCLS sera (right,
B). DNA fragments (ladders) are visualized under
ultraviolet illumination after staining with ethidium bromide.
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Figure 3.. Annexin V stain of endothelial cells treated with
control sera (left, A) or SCLS sera
(right, B). Florescence stains (arrow)
represent binding of annexin V to phosphatidylserine that translocate
from the inner face of plasma membrane to cell surface early in
apoptosis (original x 100).
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Figure 4
shows the apoptotic activity of SCLS sera compared with negative and
positive control specimens. The positive control values represent
annexin-V binding to endothelial cells exposed to 0.03%
H2O2, while the negative
controls are wells treated with control sera with Annexin-V staining.
Importantly, the apoptotic activity in three serum samples from the
first patient showed the following apoptotic activity during the time
course of hospitalization: (1) 3,597 ± 211 at hospital admission,
(2) 4,421 ± 259 in the ICU after intubation, and (3) 3,360 ± 267
when the patient was in stable condition and extubated.
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Figure 4.. The apoptotic activity of endothelial cells
exposed to SCLS sera compared with negative and positive controls.
Negative controls are wells treated with control sera with annexin-V
staining. The positive control values represent annexin-V bindings to
endothelial cells exposed to 0.03% H2O2.
Apoptotic activity is also shown in cells exposed to sera from five
shock (four sepsis and one pancreatitis) patients.
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Western blot analysis showed expression of Bcl-2 in cells exposed to
control sera, while both Bcl-2 and Bax were detected in endothelial
cells exposed to SCLS sera (Fig 5
). The relative concentration of Bax (22-kd band) was significantly
higher than Bcl-2 (25-kd band) in cells exposed to the SCLS sera.
Quantification of cellular ROS was performed in cells exposed to
either control sera or SCLS sera. A representative fluorescence imaging
of cells exposed to control serum and the serum from patient 1 is shown
in Figure 6
. Quantifying the fluorescence signal from > 200 cells for each
patient and control subject, we found that control serum did not
increase basal ROS concentrations within endothelial cells. However,
the serum from both patient 1 and patient 2 caused marked increases in
ROS that were detectable at 1 h and persisted for at least 12
h (Fig 7
).
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Figure 7.. Quantifying the fluorescence signal from > 200
cells for each patient and control subject. Control serum did not
increase ROS concentrations within endothelia cells, but the sera from
both patient 1 and patient 2 caused marked increases in ROS, which were
detectable at 1 h (p < 0.01) and persisted for 12 h
(p < 0.01).
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Discussion
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SCLS is a disease characterized by episodes of cardiovascular
shock due to accelerated, massive extravasations of plasma as a result
of altered capillary permeability. Atkinson et al9
demonstrated that during attacks, labeled albumin and plasma are
rapidly transferred from the vascular compartment. They also showed
extravasations of proteins of molecular weights as high as 900,000 d,
but mostly 
200,000, occurring during the acute attack. Thus,
profound hypoalbuminemia and hemoconcentration are invariably present
during acute SCLS attacks that limit the efficacy of available plasma
expanders in the management of this disease. The clinical presentation
of recurrent massive alteration in capillary permeability in
association with the presence of monoclonal paraprotein (gamma
globulin) is considered a characteristic manifestation of SCLS.
Another clinical characteristic common to both our patients was the
development of acute right-axis deviation during the acute attacks that
resolved with the resolution of the attack. Jacox et al10
also described this finding, but no clear mechanism has been proposed.
In our patients, pulmonary emboli were ruled out, as was acute
pulmonary hypertension due to either left myocardial dysfunction or
hypoxia. Instead, we suggest that the right-axis deviation may be
secondary to the notable increase in PVR. A likely mechanism for this
increase in PVR is the dramatic rise in hematocrit that also raises
blood viscosity.11
The etiology of the sudden increase in vascular permeability remains
unclear. Still, since the vascular endothelium is the guardian of
vascular permeability, the characteristics of this clinical syndrome
imply profound modification in vascular integrity and function.
Clarkson et al1
in 1960 induced hypotension in rats by
injecting plasma samples taken from patients during an acute SCLS
attack, suggesting the presence of a circulating factor that alters
vascular permeability.
A role for the abnormal gamma globulin in the pathogenesis has been
suggested.9
However, Zhang and colleagues12
purified the paraproteins from three patients with SCLS and
found that these proteins did not bind to cultured endothelial cells
and did not induce cytotoxicity alone, or in the presence of
neutrophils, toward cultured endothelial cells.
Other studies have suggested a possible role for
leukotrienes,13
cytokines,14
and
complement15
16
in the pathogenesis of SCLS. Rondeau et
al17
found increased production of the 5-lipoxygenase
pathway metabolites in leukocyte suspensions from SCLS patients
compared to control subjects. Such leukotrienes have been implicated in
increased capillary permeability, but their role in endothelial
cell injury (if any) remains unknown. Cicardi et
al13
found increased interleukin (IL)-2–receptor
expression on blood mononuclear cells surrounding the blood vessels
suggesting a role for IL-2 (or possibly cytokines in general).
Johansson and Löfdahl15
and Löfdahl et
al16
reported increased complement levels during SCLS
attacks, and thus tentatively interpreted their findings of increased
endothelial microvesicular bodies and pedunculated blebs as
complement-mediated endothelial injury. We did not investigate the
possible role of IL-2 in our two patients, but complement levels were
normal in both patients.
Proposed SCLS Mechanism
Loss of endothelial integrity (and hence increased capillary
permeability) can result either from (1) widening of intercellular gaps
as a result of increased intracellular calcium leading to contraction
of intraendothelial filaments, or (2) from endothelial cell injury and
destruction. In this study, we have shown a significant increase in
endothelial cell destruction by apoptotic mechanism when cells were
exposed to SCLS sera in vitro. Analysis of the corresponding
Bcl-2 gene family members showed enhanced expression of both the cell
death repressor Bcl-2 and the cell death promoter Bax proteins.
Nevertheless, the increase in Bax was greater than Bcl-2, suggesting
increased ratio of Bax to Bcl2. Increased Bax/Bcl-2 ratio has been
shown to enhance the sensitivity of cells to apoptotic
stimuli.18
The relative upregulation of the Bax gene
expression coupled with our finding of increased ROS indicates that
endothelial apoptosis observed in this study is likely the result of
mitochondrial injury stemming from an oxidation insult.
While endothelial cell apoptosis was not previously suggested as the
mechanism for SCLS. Johansson and Löfdahl,15
using
electron microscopy studies on muscle tissue of SCLS patients, did not
observe widening of interendothelial gaps while at the same time
demonstrated increased endothelial microvesicular bodies and
pedunculated blebs. These histologic features are now recognized as
signs of apoptosis. Moreover, Shimura et al19
reported that ROS induced endothelial cell injury, induced by
H2O2, is mediated by
reduction in intracellular cyclic adenosine monophosphate (cAMP) [or
efflux]. Furthermore, they showed that this injury is blocked by cAMP
elevating agents.
The above-described role for cAMP in the regulation of
endothelial injury is in many respects consistent with the
reported20
21
success of theophyline (phosphodiesterase
inhibitor) and terbutaline (ß2-agonist) in
decreasing the recurrence and severity of SCLS attacks. Hence, it is
conceivable that increasing intracellular cAMP by blocking its
degradation (theophylline) and/or by facilitating its production
(terbutaline) may slow or prevent endothelial apoptosis.
Finally, endothelial cell injury also plays a major role in other
clinical conditions resulting in capillary leak, such as septic shock,
pancreatitis, and systemic inflammatory response
syndrome.22
For example, injection of tumor necrosis
factor-
or lipopolysaccharides leads to ceramide-dependent
endothelial apoptosis in mice.23
Others24
showed that antioxidants such as aminothiol protected against
endothelial cell apoptosis that indicate a possible role for ROS
in this injury. To this end, pilot data from our laboratory show that
in vitro exposure of endothelial cells to sera from five
patients with shock (four sepsis and one pancreatitis) led to increased
apoptosis similar to that seen in SCLS patients (Fig 4)
.
The ratio of Bcl-2/Bax expression is now emerging as a crucial
determinant of cell survival particularly in the defense against
oxidative injury.25
26
The maintenance of homeostasis in
normal tissues in general reflects a balance between cell proliferation
and cell death. Our results suggest that inhibition of endothelial
apoptosis by anticaspases and/or antioxidant may have a therapeutic
value. However, further studies are needed to confirm this possible
therapeutic approach.
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Acknowledgements
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The authors thank Robert Habib, PhD, for valuable
input, and Carol Gannon for secretarial support.
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Footnotes
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Abbreviations: cAMP = cyclic
adenosine monophosphate; IL = interleukin; PVR = pulmonary vascular
resistance; ROS = reactive oxygen species; SCLS = systemic
capillary leak syndrome
Received for publication September 26, 2000.
Accepted for publication March 27, 2001.
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Abstract
Introduction
