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Pulmonary Research Laboratory, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada V6Z 1Y6
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The pulmonary vascular bed is an important
reservoir for the marginated pool of leukocytes that can be mobilized
by exercise or catecholamines. This study was designed to determine the
phenotypic characteristics of leukocytes that are mobilized into the
circulation during exercise. Twenty healthy volunteers performed
incremental exercise to exhaustion [maximal
O2 consumption
(
O2 max)]
on a cycle ergometer. Blood was collected at baseline, at 3-min
intervals during exercise, at
O2 max, and 30 min
after exercise. Total white cell, polymorphonuclear leukocyte (PMN),
and lymphocyte counts increased with exercise to
O2 max
(P < 0.05). Flow cytometric analysis
showed that the mean fluorescence intensity of L-selectin on PMN (from
14.9 ± 1 at baseline to 9.5 ± 1.6 at
O2 max,
P < 0.05) and lymphocytes (from 11.7 ± 1.2 at baseline to 8 ± 0.8 at
O2 max,
P < 0.05) decreased with exercise.
Mean fluorescence intensity of CD11b on PMN increased with exercise
(from 10.2 ± 0.6 at baseline to 25 ± 2.5 at
O2 max,
P < 0.002) but remained unchanged on
lymphocytes. Myeloperoxidase levels in PMN did not change with
exercise. In vitro studies showed that neither catecholamines nor
plasma collected at
O2 max during
exercise changed leukocyte L-selectin or CD11b levels. We conclude that
PMN released from the marginated pool during exercise express low
levels of L-selectin and high levels of CD11b.
neutrophils; cell adhesion molecules; integrins; sequestration
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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LEUKOCYTES THAT LEAVE the circulating bloodstream are delayed along the walls of microvessels, forming a sequestered or "marginated" pool that can be rapidly mobilized back into the circulation (1, 14, 16, 33). Stress, such as physical exercise and catecholamine infusion, increases the circulating leukocyte counts by mobilizing this marginated pool (11, 25, 28). Several studies have shown that the pulmonary and splanchnic microvascular beds are important reservoirs for this marginated pool (5, 14, 37). The margination of polymorphonuclear leukocytes (PMN) in the pulmonary vascular bed has been studied extensively and has been attributed primarily to their mechanical properties and to the discrepancy between PMN size and the size of pulmonary capillaries (8, 13, 42).
Several mechanisms have been proposed to explain how PMN demarginate.
Thomassen and colleagues (37) showed that an increase in pulmonary
blood flow causes demargination of leukocytes from the pulmonary
capillary bed. They suggest that the redistribution of flow to lung
regions sequestering leukocytes or changes in the mechanical properties
of leukocytes induced by the increased flow releases leukocytes from
the lung. Humoral factors, such as catecholamines, that increase during
exercise (2, 17) could influence the leukocyte-endothelial cell
interactions, resulting in the release of cells into the circulation.
Lymphocytes, granulocytes, and endothelial cells have
2-receptors, and stimulation of
these receptors diminishes the adherence of PMN to endothelial cells (6). However, blocking these receptors with -blockers only partially
reduces the leukocytosis of exercise (11).
The cell adhesion molecules, which are expressed on the surface of
leukocytes and endothelial cells, play a pivotal role in leukocyte-endothelial cell interaction (3, 19, 30, 43). This
interaction is an early and requisite event in inflammation, contributes to the margination of PMN in activated vascular beds, and
plays a key role in lymphocyte homing and recirculation (3, 30, 43).
L-selectin (CD62L) and the
2-integrins on the surface of
leukocytes play an important role in this leukocyte-endothelial cell
interaction (3). These molecules undergo quantitative and qualitative
changes in response to various stimuli and could be involved in the
leukocyte-endothelial cell interactions that contribute to margination
and demargination of leukocytes. Immature PMN released from the bone
marrow have been shown to preferentially marginate in lung capillaries
(26, 39). Furthermore, studies from our laboratory have shown that
younger PMN released from the bone marrow express higher levels of
L-selectin (39, 40) and lower levels of the integrin CD18 on their
surface (21).
On the basis of these findings, we reasoned that the marginated PMN should be enriched, with younger cells expressing high levels of L-selectin and low levels of CD18. The present study was designed to test this hypothesis by measuring the surface density of the adhesion molecules L-selectin and CD18/CD11b on leukocytes mobilized into the circulation during exercise. We used a model of short-term intense exercise that has been shown to release leukocytes from the marginated pool into the circulation (11, 25, 28).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. Twenty healthy infection-free volunteers, 25-48 yr of age, were recruited for the study. Informed consent was obtained from all subjects, and the Human Experimentation Committee of the University of British Columbia approved the study. All subjects had participated in some form of recreational or competitive sport, and their current exercise activity was graded as equivalent to grade 1 (running or other aerobic exercise for <1 h/wk), grade 2 (1-3 h/wk), grade 3 (4-6 h/wk), or grade 4 (>6 h/wk) (7).
Experimental protocol.
All subjects were studied in the morning between 8 and 10 AM and asked
to refrain from exercise during the 24 h before the study. All subjects
were nonsmokers, used no medication, and consumed a light breakfast in
the morning ~2 h before the exercise. An intravenous indwelling
18-gauge catheter was placed in a large vein in the forearm for blood
sampling and was maintained open by flushing with normal saline.
Baseline samples were taken 15 min after placement of the catheter and
every 3 min while cycling, at maximal
O2 consumption
(O2 max), and 30 min
after the exercise was discontinued. Blood samples were collected into
5-ml sterile tubes containing potassium EDTA (Becton Dickinson) and
analyzed within 1 h of collection. Blood was also collected in separate tubes to obtain plasma (EDTA tubes).
15 min. The average time to
O2 max was
~10 min. Criteria for attaining
O2 max included a
plateau in O2 consumption, a heart
rate close to the subject's age-related maximum and no further
increase with increasing workload, and signs of exertional intolerance
(inability to maintain required pedal rhythm, and fatigue).
Leukocyte counts. The total leukocyte count was determined by a Sysmex cell counter (model E4000, Toa Medical Electronics, Kobe, Japan), and the differential counts and band cells counts were done on Wright-stained blood smears. All counts of circulating leukocytes were adjusted for changes in hematocrit during exercise according to the following equation: Ca = Ct = n × Ht = 0/Ht = n, where Ca is the adjusted count, Ct = n is the observed count at time n, Ht = 0 is the hematocrit at time 0 or baseline before the start of exercise, and Ht = n is the hematocrit at time n. The blood smears were evaluated in a blinded fashion by evaluating 100 leukocytes in randomly selected fields of view.
L-selectin and CD11b expression on leukocytes. Blood collected in EDTA was used to immunolabel circulating leukocytes for the presence of surface L-selectin, CD18, and CD11b. A whole blood method was used to prepare cells for flow cytometry using a commercially available kit (Coulter Clone, Coulter Immuno, Hialeah, FL). Briefly, 100 µl of EDTA blood were incubated for 10 min with the anti-CD18/CD11b monoclonal antibody at 1.0 µg/ml final concentration (DAKO Laboratories, Copenhagen, Denmark) or the anti-L-selectin monoclonal antibody Leu-8 at 1.2 µg/ml final concentration (Becton-Dickinson, Mississauga, ON, Canada). All experiments were performed at room temperature and with use of the buffer provided by the manufacturer. Isotype nonimmune mouse IgG (DAKO Laboratories) in concentrations similar to the primary antibody were used as negative controls. After they were labeled with the primary antibody, cells were washed and incubated with a FITC-conjugated goat anti-mouse secondary antibody at 0.2 µg/ml final concentration for 10 min (DAKO Laboratories). Red blood cells were lysed with Immunolyse (Coulter Immuno), and the remaining leukocytes were washed twice and fixed with 1% paraformaldehyde. As a positive control, cells were incubated with f-Met-Leu-Phe (fMLP; Sigma Chemical, St. Louis, MO; 10 nM final concentration) before they were labeled for L-selectin, CD11b, or CD18, as described above. Flow cytometry was performed using analysis gates for PMN and lymphocytes from typical forward and side-angle light-scattering patterns (Profile Epics XL, Coulter Electronics). A total of 5,000 cells/specimen were evaluated, and the results are expressed as the mean fluorescence intensity (MFI).
Circulating mediators and leukocyte L-selectin and CD11b
expression.
Baseline blood was exposed to autologous plasma obtained at
O2 max to determine
the possible effect of circulating factors released during exercise on
the expression of surface L-selectin and CD11b of leukocytes. Plasma
was obtained by centrifugation of EDTA blood (2,000 rpm or 750 g) for 10 min. We incubated 100 µl
of baseline whole blood (EDTA) with a similar volume of 1:100, 1:10,
1:5, 1:2, or 1:1 dilution or a full-strength plasma (diluted in PBS, pH
7.4) for 15 min at 37°C. Cells were washed with PBS and
centrifuged, the supernatant was removed, and the cell pellet was
resuspended in 200 µl of PBS. Immunofluorescent staining of leukocytes for surface expression of L-selectin and CD11b was done as
described above.
Catecholamines and leukocyte L-selectin and CD11b expression. Baseline blood was exposed to incremental doses of epinephrine or norepinephrine to determine the effect of these two stress hormones on the surface expression of L-selectin and CD18/CD11b of leukocytes. Whole blood was incubated with 0.25, 0.5, 1, 10, 100, or 1,000 ng/ml (final concentration) of epinephrine and norepinephrine for 15 min at 37°C. Levels of these hormones vary from 0.2 to 3 ng/ml during exercise (2). The cells were then washed with PBS and centrifuged, the supernatant was removed, and the cell pellet was resuspended in 200 µl of PBS. Immunofluorescent staining of leukocytes for surface expression of L-selectin and CD11b was done as described above.
Myeloperoxidase content of PMN.
Myeloperoxidase (MPO) content of leukocytes was determined by using the
substrate diaminobenzadine (DAB; Sigma Chemical) and stained on slides
prepared from leukocyte-rich plasma (LRP). Blood used for the
preparation of LRP was collected in acid-citrate-dextrose. The
erythrocytes were sedimented by addition of 4% dextran (average relative mol wt 267,000; Sigma Chemical) in PMN buffer (in mM: 138 NaCl, 27 KCl, 8.1 Na2HPO47H2O,
1.5 KH2PO4,
and 5.5 glucose, pH 7.4). The resulting LRP was cytospun at 180 g for 4 min with a Cytospin 2 (Shandon
Lab Products, Cheshire, UK) to obtain a monolayer of cells on slides
precoated with 3-aminopropyltriethoxysilane. Slides were air dried and
fixed in 1% paraformaldehyde at 4°C for 30 min. Slides were washed
with distilled water, and cells were permeabilized for 15 min at room
temperature with
N-octyl--D-glucopyranoside (Sigma Chemical; 6 µg/ml) diluted in Tris-buffered saline (TBS), pH
7.4. Slides were washed twice with TBS and treated with DAB substrate
(1 ml of 5 mg/ml DAB diluted in 9 ml of TBS, pH 7.4, with 0.033 ml of
3%
H2O2)
in the dark for 60 min at room temperature. Slides were washed twice in
TBS, counterstained with Mayer's hematoxylin for 2 min, dehydrated,
and coverslipped. The intensity of staining was evaluated by grading
PMN as highly, intermediately, or weakly stained (see Fig. 7). One
hundred cells selected in random fields were evaluated from blood
samples collected at all time points. This grading system was evaluated
for inter- and intraobserver variability.
Data analysis. Unpaired Student's t-test was used to compare adhesion molecules at baseline and after fMLP stimulation. To assess the effect of exercise on temporal data, an ANOVA for repeated measures was used, and Bonferroni corrections were made for multiple comparisons. Values are means ± SE; P < 0.05 was considered significant.
The inter- and intraobserver variations in the grading of MPO staining were evaluated by calculating the Pearson coefficient of mean-square contingency (R2) for each grade and expressing R2 as a fraction of the maximum possible value (R2max), which represents the value of the Pearson
2
coefficient if there is 100% agreement in the grading score between or
within observers; thus R2max = ±0.82 (32).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Table 1 shows the demographic
characteristics of the study population. The study group was
predominantly men (15:5 ratio of men to women) with a fitness level of
2.8 ± 0.2 (grades 1-4, see
METHODS) and an average
O2 max of 3.8 ± 0.2 l/min.
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Leukocyte counts.
Peripheral blood total leukocytes increased from 4.9 ± 0.4 at
baseline to 8.7 ± 0.9 × 109/l at
O2 max and decreased to
6.9 ± 0.8 × 109/l at 30 min after exercise. This was due to a rise in PMN and lymphocyte
counts, with a more pronounced lymphocyte response (Fig.
1). A small but nonsignificant
(P > 0.05) increase in circulating band cells was observed during the exercise protocol (Fig. 1).
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CD11b and L-selectin expression on leukocytes.
Figure 2 shows a representative flow
cytometric profile of PMN and lymphocytes for L-selectin and CD11b at
baseline and O2 max. L-selectin expression on circulating PMN gradually decreased during exercise and was lower than baseline at
O2 max and after
exercise (P < 0.05; Fig.
3). CD11b increased during exercise to peak
at O2 max
(P < 0.002) and then declined after
exercise but did not return to baseline levels (Fig. 3). A similar
increase was observed for CD18 (data not shown). The drop in
L-selectin and the increase in CD11b were smaller than those
achieved by cell activation by use of the chemoattractant fMLP (Fig.
4). CD11b expressionon lymphocytes did not
change, but L-selectin decreased (P < 0.05) during and after exercise (Fig.
5).
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Circulating mediators and leukocyte L-selectin and CD11b expression.
Incubating whole blood obtained at baseline with incremental
concentrations of epinephrine or norepinephrine did not significantly change the expression of CD11b or L-selectin on PMN (Fig.
6). Similar results were obtained with
lymphocytes (data not shown). Baseline blood incubated with increasing
dilutions of plasma obtained at
O2 max showed no
changes in CD11b or L-selectin on PMN or lymphocytes.
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MPO in PMN.
The variability of PMN staining for MPO is shown in Fig.
7. This variability allows us to grade the
intensity of MPO staining of circulating PMN as high, intermediate, or
low. R2max for inter- and
intraobserver variability was >0.75. Figure
8 shows the results of this grading method.
No significant changes were observed in PMN MPO activity during or
after exercise. This finding was confirmed in a subset of subjects
(n = 5) by using flow cytometry and
monoclonal antibodies against human MPO (MFI = 2.8 ± 0.9, 3.2 ± 1, 2.2 ± 1.1, 2.9 ± 0.8, and 2.5 ± 1.2 at baseline, 3 min of exercise, 6 min of exercise,
O2 max, and after
exercise, respectively).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Exercise and catecholamine infusion increase blood leukocyte counts
(11, 25, 28). This leukocytosis is caused by mobilization of the
marginated pool of leukocytes and not bone marrow release of
leukocytes. This study shows that exercise mobilized PMN into the
circulation without increasing the band cell counts, excluding bone
marrow release as a reason for the increase in circulating PMN counts.
It also shows that the mobilized PMN express lower levels of L-selectin
and higher levels of CD11b on their surface than before exercise.
Lymphocytes mobilized into the circulation during exercise also express
low levels of L-selectin. In vitro incubation of leukocytes with
catecholamines or plasma collected at
O2 max did not change
the adhesion molecules on PMN or lymphocytes. This suggests that
circulating factors in the blood during acute maximal exercise are not
responsible for the changes we observed in leukocyte cell adhesion molecules.
In this study we used exercise to mobilize leukocytes from the
marginated pool and an incremental exercise protocol of 15 min. This
short-term protocol was used, because endurance exercise has been
associated with changes in PMN adhesion molecules compatible with
release of PMN from the bone marrow (24). Although Kurokawa and
colleagues (24) did not measure band cell counts, the changes they
report in PMN L-selectin with 1 h of endurance exercise are similar to
those we previously showed to be associated with active bone marrow
release (26, 38, 39). Total white cell, PMN, and lymphocyte counts
increased during the exercise (Fig. 1), but there was no accompanying
increase in circulating band cell counts during or after exercise
compatible with bone marrow release of PMN. These findings are
consistent, in that the increase in leukocyte counts is largely due to
the mobilization of leukocytes from the marginated pool.
Several studies have shown that the pulmonary circulation is an
important reservoir of marginated leukocytes (5, 14, 37). In the
present study we showed an increase in CD11b expression on circulating
PMN during incremental exercise to
O2 max (Figs. 2 and 3),
suggesting mobilization of PMN expressing high levels of CD11b from the
marginated pool. This is in contrast to findings from Kurokawa and
colleagues (24) that showed no changes with endurance exercise. A
possible explanation for this discrepancy is that during endurance
exercise an equilibrium develops between PMN expressing high levels of
CD11b marginating and demarginating in the lung. Because an increase in
surface density of CD11b signifies PMN activation (19), mobilization of
PMN expressing high levels of CD11b during exercise suggests that
activated PMN are preferentially delayed in lung microvessels. In
normal infection-free subjects, these could be PMN activated during
their intravascular life when they encounter mildly activated vascular
beds such as the upper respiratory tracts, bladder, and large bowels.
Changes in PMN deformability associated with mild cell activation (8,
7, 13-15, 42) are most likely responsible for the preferential
margination of PMN expressing high levels of CD11b in the lung. We
suspect that the increase in pulmonary blood flow during exercise
(16, 33, 37) mobilizes PMN expressing high levels of CD11b from the lung.
Alternatively, local factors in the pulmonary capillaries could activate PMN in the lung. The process of demargination may also contribute to changes in cell adhesion expression. Recent studies from our laboratory showed that mechanical deformation of PMN increases CD11b expression (20). PMN have to negotiate ~50-60 pulmonary capillary segments from the arterial to the venous side of the pulmonary circulation (8, 13, 14). The average pulmonary capillary segment size is 5-8 µm, which would cause minimal PMN deformation, but 10-15% of capillary segments are <5 µm in diameter, which requires PMN to deform. This deformation is associated with an increase in CD11b expression (20, 41, 43). Furthermore, the increase in pulmonary blood flow during exercise would increase the likelihood that PMN would encounter small capillary segments and also increase shear forces on the PMN. Both factors have been shown to increase PMN CD11b expression (9, 20).
Circulating mediators such as catecholamines have been shown to
increase during exercise (2, 17), but incubation of whole blood with
exercise-related or pharmacological concentrations of epinephrine and
norepinephrine did not alter the expression of CD11b on PMN (Fig.
6). Furthermore, exposing baseline whole blood to plasma collected at
O2 max also failed to
change CD11b expression on leukocytes. These studies suggest that
circulating mediators generated during exercise are unlikely to be
responsible for the increase in CD11b.
Gray and colleagues (12) showed that intense interval running induced granulocyte activation measured as the release of PMN elastase from the primary granules. This type of exercise has been shown to cause muscle damage and PMN activation (29, 31). We have measured MPO, an enzyme in the primary granules, of PMN and could not demonstrate any change induced by the short-term exercise protocol we used (Fig. 8).
The drop in L-selectin expression on PMN during exercise (Figs. 2 and
3) agrees with the observations of Kurokawa and colleagues (24), who
showed a decline in L-selectin on circulating PMN during 1 h of
endurance exercise at 60%
O2 max (24). L-selectin has been shown to be important in the margination of PMN along the
vessel wall in postcapillary venules in the systemic and pulmonary circulations (3, 22, 23, 43). Kuebler and colleagues (22) showed that
leukocyte retention in pulmonary arterioles, venules, and capillaries
depends on the interaction of leukocytes with capillary endothelium. By
blocking selectin-dependent pathways with fucoidin, the transit time of
leukocytes through capillaries is reduced by ~62%, suggesting that,
in addition to mechanical factors, the selectins contribute
significantly to leukocyte retention in the lung (22). The release of
these leukocytes from the marginated pool during exercise may be
associated with a loss of L-selectin. Alternatively, PMN
expressing low levels of L-selectin may tend to marginate
preferentially. We previously showed that L-selectin levels on PMN
decline as they age in the circulation (38). These older PMN also
express higher levels of CD18 (38), produce more oxygen radicals when
stimulated (34), and could potentially be more harmful to the host when
activated in the lung by stimuli such as cigarette smoke.
Exercise causes a brisk lymphocytosis and a decrease in the expression of L-selectin on circulating lymphocytes (Figs. 2 and 5), suggesting that lymphocytes mobilized from the marginated pool of cells express low levels of L-selectin. The majority of B and virgin T lymphocytes express L-selectin, whereas only a subpopulation of memory T cells and NK cells are L-selectin positive (36). L-selectin is also weakly expressed by the majority of splenic lymphocytes (35). Mobilization of these lymphocytes expressing low levels of L-selectin from the spleen or the lung could result in the drop in L-selectin that we observed during exercise.
The splanchnic circulation receives 20% of the cardiac output, and the spleen and liver are the major organs that contribute to the marginated pool of leukocytes in the splanchnic bed (10, 18). The splenic sinusoids are also the major site for removal of older, activated, and apoptotic PMN from the circulation (4, 10). Mobilization of these older PMN from splenic sinusoids during exercise could also contribute to the drop in L-selectin and the rise in CD11b on PMN in circulating blood during exercise. The relative contribution of these leukocytes released from the splanchnic vascular bed on the adhesion molecule profile of circulating leukocytes during exercise needs to be determined.
We have shown that PMN demarginating during exercise express lower levels of L-selectin and higher levels of CD11b than their circulating counterparts. Lymphocytes that demarginate during exercise express lower levels of L-selectin and may represent the mobilization of a subpopulation of memory T and NK cells. The low levels of L-selectin on demarginated PMN suggest that these cells are older. The high levels of CD11b on demarginated PMN support the hypothesis that these PMN are mildly activated. These findings underline the differences in phenotypic characteristics of circulating and marginated leukocytes. We speculate that these characteristics play an important role in leukocyte-mediated tissue inflammation and injury.
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ACKNOWLEDGEMENTS |
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We thank Dr. Belzberg for the use of exercise laboratory facilities, Stuart Greene for photography, and Lorri Verbrugt for statistical analysis.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: S. van Eeden, Pulmonary Research Laboratory, 1081 Burrard St., Vancouver, BC, Canada V6Z 1Y6 (E-mail: svaneeden{at}prl.pulmonary.ubc.ca).
Received 11 August 1998; accepted in final form 18 November 1998.
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TOP
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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