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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Interleukin-6 (IL-6) is an important mediator of both the hepatic and the bone marrow components of the acute-phase response. Previous studies from our laboratory have shown that cells released into the circulation from the marrow preferentially sequester in the lung. The present study was designed to examine the mechanism of this sequestration using a single dose of recombinant human IL-6 to stimulate the marrow in rabbits. Marrow release was monitored by labeling polymorphonuclear leukocyte (PMN) precursors in the marrow with the thymidine analogue, 5'-bromo-2-deoxyuridine (BrdU), 24 h before IL-6 treatment. This treatment caused a neutrophilia that was associated with the increase of circulating BrdU- labeled PMN (PMNBrdU) and morphometric studies confirmed that PMNBrdU released from the marrow preferentially sequestered in the lung microvessels compared to unlabeled PMN. IL-6 treatment increases PMN F-actin content (p < 0.05) that was not due to cell activation by IL-6. In vitro studies show that IL-6 treatment decreased the deformability of circulating PMN (p < 0.05). These studies confirm that IL-6 treatment causes an accelerated release of PMN from the bone marrow and shows that these newly released PMN have high levels of F-actin, are less deformable, and preferentially sequester in lung microvessels.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Interleukin-6 (IL-6) is a 26-kD cytokine with pleiotropic activities in both the immune and hematopoietic systems. It is produced in response to inflammatory stress and is one of the major regulators of the acute-phase response (1). Elevated blood levels of IL-6 have been implicated in the pathogenesis of sepsis, acute respiratory distress syndrome (ARDS) (2), and multiorgan failure (3) as well as in chronic inflammatory conditions such as rheumatoid arthritis (4). IL-6 is produced by different cell types that include T cells, macrophages, and fibroblasts and mediates a wide variety of biological activities (5, 6). It enhances differentiation and proliferation of multipotential hematopoietic progenitors in vitro (6, 7). It stimulates the clonal growth of granulocyte and macrophage progenitor cells, and in synergy with interleukin-3 (IL-3), stimulates the growth of multipotential hematopoietic progenitor and spleen cell cultures (7, 8). IL-6 produced by stromal cells in the bone marrow induces the proliferation and differentiation of hematopoietic cells in the bone marrow microenvironment (9). Therefore, IL-6 produced either in the bone marrow (9) or at distant sites and released into the systemic circulation could have a profound effect on the production and the kinetics of polymorphonuclear leukocytes (PMN).
PMN are important in the pathogenesis of acute lung injury (10). The initiating event in this form of injury is sequestration of PMN in microvessels of the lung (10), which is influenced by the size, deformability of PMN, and adhesive qualities of PMN and endothelial cells. The discrepancies between the size of PMN and pulmonary capillaries segments (10) dictate the need for PMN to deform to get through pulmonary capillaries. Differences in deformability between PMN and erythrocytes (red blood cells, RBC) result in pulmonary transit times of about 60 s for PMN compared with 1 s for RBC (11). The multisegmental nature of the pulmonary capillary bed allows RBC to stream around slower moving PMN and concentrates PMN with respect to RBC in pulmonary capillaries compared with peripheral blood (10, 11).
Inflammatory stimuli further increase the concentration of PMN in pulmonary capillaries by decreasing their deformability and increasing their adhesiveness to endothelial cells. The decrease in deformability is mediated by a rapid assembly of filamentous F-actin from soluble G-actin at the cell periphery, which increases the rigidity and viscosity of PMN (12, 13). The increased adherence between PMN and the endothelial cells is initiated by selectins that mediate rolling and slowing of PMN followed by integrins that induce firm adhesion to the endothelial cells (14). This prolonged sequestration of PMN in the lung microvessels provides the opportunity for them to damage the endothelium (14).
The present study was designed to examine role of IL-6 on the factors that contribute to PMN sequestration in the lung. It is based on previous studies that show IL-6 induces a release of PMN from the bone marrow (17) and the use of the thymidine analog, 5'-bromo-2-deoxyuridine (BrdU) to label the dividing PMN in the bone marrow (18). These methods allow the identification of PMN recently released from the bone marrow into the circulation and their sequestration in the lung (19). We also measured PMN F-actin content and deformability, two important factors determining PMN sequestration, after IL-6 treatment.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
This study was approved by the Animal Experimentation Committee of the University of British Columbia and was based on 40 female New Zealand White rabbits with an average weight of 2.2 ± 0.2 kg.
Experimental Design
BrdU, 100 mg/kg (Sigma Chemical, St. Louis, MO), was infused intravenously into rabbits. Twenty-four hours later, recombinant human IL-6 (Lot No. 118H0227, purity > 97%, endotoxin < 0.1 ng/µg IL-6) (Sigma) was infused intravenously (2 µg/kg) and control rabbits received an equivalent volume of saline. This dose of IL-6 (20) given was based on levels during major stress such as surgery (21, 22). Blood samples were collected at regular intervals and animals were followed for 48 h. To determine PMN sequestration in the lung, rabbits were sacrificed at 12, 24 and 48 h following IL-6 or saline treatment and lungs were processed for morphometric analysis as previously described (19, 23). Bone marrow smears were air dried, fixed in methanol, and stained with May-Grünwald-Giemsa. Differential counts of myeloid or erythroid cells were performed on at least 500 cells/smear using standard morphologic criteria (24). All slides were coded and examined without knowledge of the group.
Immunocytochemical Detection of BrdU-labeled PMN
Cytospin slides were stained by the alkaline phosphatase and anti- alkaline phosphatase (APAAP) method (18, 25) using anti-BrdU monoclonal antibody Bu20a (26) (DAKO, Copenhagen, Denmark) to determine the fraction of BrdU-labeled PMN (PMNBrdU) (18). PMN with any nuclear stain for BrdU were counted as positive. PMNBrdU were evaluated on a Zeiss Universal light microscope in random fields of view. On cytospins, 100 PMN were counted and the percentages of PMNBrdU were determined; if less than 10% were positive 500 cells were counted.
Morphologic Studies of Lung Tissue
The lung slices stained for BrdU were point counted with the images captured by a spot digital camera (Microspot, Nikon Inc., Tokyo, Japan), and then analyzed using a point-counting grid of 500 points that was superimposed onto the captured image and image analysis software (Image Pro Plus; Media Cybernetics, Silver Spring, MD). Twenty-four random fields of view/animal were evaluated. The number of PMN and PMNBrdU sequestered in the lung was calculated as previously described (19, 23, 27) and results were expressed as the number of PMN/ml of tissue. The density of the point counting grid and the number of fields counted were selected to maintain the coefficient of error of the estimate of the volume below 0.1 (28).
F-actin Content and CD18 Expression of PMN
F-actin content (27) and surface CD18 (anti-CD18 monoclonal antibody 60.3, a kind gift of Dr. J. Harlan) of circulating PMN were measured using a whole blood method (29) for flow cytometry and a commercially available kit (Coulter Clone; Coulter Immuno, Hialeah, FL).
PMN were activated with 10
7 M formylmethionylleucylphenylalanine (FMLP) for 45 s and the reaction was stopped by 2% paraformaldehyde. F-actin content and CD18 surface expression were measured
using a Profile Epics 2 (Coulter Electronics, Hialeah, FL) with analysis gates for PMN selected from typical forward and side angle light
scattering. A total of 3,000 cells/specimen were evaluated and results
were expressed as the mean fluorescence intensity.
F-actin Distribution in PMN
The distribution of F-actin was examined in purified (18) PMN at 0, 6, 12, and 24 h after either IL-6 (2 µg/kg intravenous injection, n = 3) or
saline (n = 3) treatment. FMLP (107 M) for 45 s was used as agonist,
cells were fixed with 3% paraformaldehyde, and cells were cytospun
(120 × g for 7 min) onto 3-aminopropyl-triethoxysilane-coated slides,
plunged into cold (
20°C) acetone for 5 min, and dried for 30 min.
After rehydration with PBS, cells were stained with 1 U/ml of BODIPY-phallacidine (Molecular Probes Inc., Eugene, OR), mounted in 1,4-diazabicyclo(2.2.2) octane antifading solution, and examined with a fluorescence microscope.
In Vitro Exposure to IL-6
To evaluate the direct effect of IL-6 on F-actin contents and CD18 expression of PMN, we exposed PMN in whole blood in vitro to increasing doses (0, 1, 3, 10 and 30 ng/ml for 10 min) of IL-6. These doses represent the range observed in this study. Surface CD18 and F-actin
were measured before and following PMN activation with 107 M
FMLP for 45 s using a flow cytometer as described above.
Deformability Assay
PMN deformability was assessed by measuring the pressure needed to
pass PMN through polycarbonate filters with a uniform pore diameter of
5 µm (AMD Manufacturing Inc., Mississauga, ON, Canada) as previously
described (27). Blood was collected from rabbits 12 h following treatment
with IL-6 (2 µg/kg, n = 3) or saline (n = 3). Four groups were studied: (1)
control-PMN, (2) control PMN + FMLP group (control PMN were stimulated with 107 M FMLP for 45 s prior to filtration), (3) IL-6-treated
PMN, and (4) IL-6-treated PMN + FMLP group (IL-6-treated PMN
were stimulated with 107 M FMLP for 45 s prior to filtration).
Statistical Analysis
All values are expressed as mean ± standard error of the mean (SEM). Analysis of variance (ANOVA) for repeated measures was used for continuous data. The effect of multiple comparisons was corrected using the Bonferonni method (30). Total PMN number in tissue and the percentage of PMNBrdU in tissue were analyzed using a two-way and one-way ANOVA, respectively, with blocking on animals. Pressure generated during the filtration study was analyzed using paired two-tailed t tests of areas under the pressure curves. Statistical significance was defined as a p-value of less than 0.05.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Effect of IL-6 on the Release of PMN from the Bone Marrow
Leukocyte in the circulation. Figure 1 shows the effect of IL-6 on white blood cells (WBC), PMN, and band cell counts. Baseline WBC, PMN and band cell counts were similar in the IL-6 and control groups. IL-6 caused a rapid increase in WBC counts (8.4 ± 0.5 × 109/L at baseline to 11.0 ± 0.8 × 109/L at 3 h after IL-6 administration), a temporary decrease in WBC counts at 6 h (9.9 ± 0.5 × 109/L), which was followed by a second increase (10.7 ± 0.5 × 109/L, p < 0.05) at 9 h (Figure 1A). This biphasic response was also seen for PMN (3.8 ± 0.2 × 109/L at baseline to 7.0 ± 0.6 × 109/L at 3 h (p < 0.05), 5.9 ± 0.3 × 109/L at 6 h, and 6.5 ± 0.3 × 109/L at 9 h). PMN counts returned to the baseline values by 48 h (Figure 1B). The percentage of nonsegmented PMN (band cells) increased from 4.0 ± 1.0% at baseline to 8.5 ± 1.4% at 9 h (p < 0.05) and returned to the baseline values by 24 h (data not shown). The number of band cell in the circulation followed the same pattern (1.5 ± 0.4 × 108/L at baseline to 5.7 ± 1.0 × 108/L at 9 h, p < 0.05 at 9 and 12 h) and returned to the baseline by 36 h (Figure 1C). WBC, PMN, and band cell counts did not change over the study period in the control animals.
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Release of PMNBrdU into the circulation. Figure 2 shows the percentage (Figure 2A) and the number (Figure 2B) of PMNBrdU in the circulation after IL-6 administration. PMNBrdU appeared in the circulation at 27 h after labeling of the bone marrow, rapidly rose, and peaked between 24-36 h (IL-6 group), and 48 h (control group). Both the number and percentage of PMNBrdU in the peripheral blood of IL-6-treated animals were higher at 9, 12, and 24 h compared with the control animals (Figures 2A and 2B, p < 0.05).
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PMNBrdU in the Bone Marrow
The percentages of PMN and PMNBrdU in the bone marrow are shown in Table 1. IL-6 treatment decreased the percentage of PMN in the bone marrow at 12 h compared with the control group (p < 0.05, Table 1). The percentage of PMNBrdU in the bone marrow increased at 12 h in the IL-6 group compared with the control group (p < 0.05 at 12 h, Table 1).
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PMN Sequestrated in the Lung
The total numbers of sequestrated PMN in the lung of each group are shown in Figure 3A. At 12 h after treatment more PMN sequestered in the lung of IL-6-treated animals (2.8 ± 0.4 × 108/ml tissue) compared with control animals (1.5 ± 0.3 × 108/ml tissue, p < 0.05). The percentage of PMNBrdU in the lung is shown in Figure 3B. Lung tissues in the IL-6-treated group show larger percentages of PMNBrdU than those in the control group at 12 and 24 h, (p < 0.05, Figure 3B). The percentage of PMNBrdU in the lung increased from 12 to 24 h in the IL-6 group (p < 0.05) and from 24 to 48 h in the control group (p < 0.05, Figure 3B). The number of PMNBrdU sequestered in the lung is shown in Figure 3C. In the IL-6-treated group the number of PMNBrdU in the lung increased from 12 to 24 h and then decreased to 48 h (p < 0.05, Figure 3C). To determine whether PMNBrdU preferentially sequester in the lung, we compared the fraction of PMNBrdU in the peripheral blood and lung capillaries. Figure 4 shows the percentage of PMNBrdU in peripheral blood and lung capillaries in the IL-6-treated (Figure 4A) and control groups (Figure 4B). IL-6 treatment increased the percentage of PMNBrdU in the lung compared with peripheral blood at 12 to 24 h (p < 0.05, Figure 4A) with no difference in the control group, suggesting preferential sequestration of PMNBrdU in the lung of IL-6-treated animals. Table 2 compares the number of PMN in 1 ml of lung tissue to the number in 1 ml of peripheral blood and shows that IL-6 treatment enriched BrdU-labeled cells at 12 and 24 h but not unlabeled cells.
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Effect of IL-6 on F-Actin Contents and CD18 Expression on Circulating PMN
Figure 5A shows the change in F-actin contents of the cells
sampled from the peripheral blood 24 h before and at the time points indicated after the animals were treated with IL-6. This shows that IL-6 treatment was associated with a rise in F-actin contents that peaked at 12 h and fell back to control levels 48 h
after the animals received IL-6. Figure 5B shows the effect of
treating the cells with 107 M FMLP for 45 s prior to measuring the F-actin contents and demonstrates that this treatment
raised the baseline measurements of the cells for both control
and IL-6-treated animals but did not change the pattern of
response produced by IL-6. The ratio of baseline to activated
F-actin was similar between control and IL-6-treated groups,
demonstrating that notwithstanding the higher baseline PMN
F-actin content with IL-6 treatment, they increase their F-actin content when stimulated as well as control PMN. The CD18 expression on PMN did not change at any time point following
IL-6 treatment (data not shown). Figure 6 shows the distribution of F-actin in PMN. These results showed that the distribution of F-actin was the same at 12 h in both IL-6-treated (Figure 6A) and control cells (Figure 6B) and that 45 s of FMLP
treatment increased F-actin and redistributed it to form clusters in a rim in the submembranous region in both IL-6-treated (Figure 6C) and control cells (Figure 6D).
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Effect of IL-6 on PMN In Vitro Exposure
Figure 7 shows the F-actin contents in PMN exposed to IL-6 (0 to 30 ng/ml) in vitro for 10 min. IL-6 treatment had no effect on the F-actin content either at baseline or following FMLP treatment (Figure 7). CD18 expression on PMN also did not change with IL-6 treatment in vitro (data not shown).
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Deformability of PMN
The pressure required to pass PMN through 5-µm pore polycarbonate membrane filters was higher with PMN collected 12 h after IL-6 treatment than control animals. This change was characterized by a more rapid upslope and higher plateau pressure. FMLP treatment of PMN further increased the pressure in both IL-6-treated and control animals (Figure 8). The plateau pressures of cells taken from the saline and IL-6-treated animals at 12 h were 10.0 ± 0.9 cm H2O and 16.3 ± 0.8 cm H2O, respectively, and that was higher in the IL-6-treated group (p < 0.05). Pretreatment of these cells with FMLP further increased these plateau pressures in both the saline-treated animals (21.9 ± 1.4 cm H2O, p < 0.05) and IL-6-treated animals (22.2 ± 0.6 cm H2O, p < 0.05).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study shows that IL-6 induces an accelerated release of PMN from the bone marrow and preferential sequestration of these cells in lung capillaries. This excess sequestration in the lung was associated with an increase in their F-actin content and a decrease in deformability of cells in the circulating blood. These changes were not due to IL-6-induced activation of peripheral blood cells suggesting that IL-6 promoted the release of PMN from the bone marrow with high levels of F-actin.
Our previous studies have shown that labeling of the dividing PMN in the bone marrow with BrdU allowed quantification of the bone marrow response and evaluation of the behavior of the PMN released into the circulation (18, 19, 31). The present study shows that IL-6 accelerates the release of PMN from the bone marrow between 9 and 24 h after treatment (Figure 2) and this corresponds to the second peak of circulating PMN at 9-12 h (Figure 1B) and the increase in band cells in the circulation (Figure 1C). The biphasic neutrophilia following a single intravenous injection of IL-6 was first reported by Ulich and colleagues (24) in rats. These workers showed that IL-6 induced myeloid proliferation in the bone marrow suggesting that the bone marrow stimulation is an important reason for the neutrophilic response following IL-6 treatment. We confirmed this finding in rabbits (17) and showed that the first peak results from demargination of PMN and the second peak results from an accelerated release of PMN from the bone marrow.
The results of the present study extend these observation by showing that IL-6 enhanced sequestration of PMN in the lung (Figure 3A) and this was characterized by the preferential sequestration of immature (Figures 1B and 1C) PMN newly released from the bone marrow (Figure 4A, p < 0.05). The sequestration of PMN in the lung is dependent on their size, deformability, and the adhesive qualities of both PMN and endothelium (10, 11, 13, 32). PMN must deform to negotiate the pulmonary capillary bed because of the discrepancy between their size and that of the pulmonary capillary segments (11, 33). Granulocytes from the bone marrow maturation pool are larger and less deformable than their circulating counterparts (32), and studies from our laboratory have shown that bone marrow stimulation releases PMN into the circulation that are less deformable (23). It is currently unclear how long these immature cells maintain this increased stiffness after they enter the circulation, and our results (Figures 3 and 4) show that the preferential sequestration of immature PMN peaked at 12 h and lasted for at least 24 h following IL-6 treatment before falling back to control levels at 48 h. This suggests that PMN released from the bone marrow by IL-6 treatment preferentially sequester in lung capillaries because they are less deformable than the more mature circulating PMN in the circulation.
The increase in sequestration of immature PMN in the lung at 12-24 h (Figure 4) corresponds to an increase in F-actin contents in circulating PMN following IL-6 treatment (Figure 5). F-actin is generated from G-actin during PMN activation (12, 13). Our studies, using CD18 as a marker of cell activation, indicate that circulating PMN were not activated by IL-6 treatment administered either in vivo (data not shown) or ex vivo (data not shown). The fact that the increase of F-actin contents in circulating PMN was slow (Figure 5) and corresponds to the increased bone marrow release of PMN (Figures 1 and 2) suggests that IL-6 releases PMN that contain higher levels of F-actin. Klut and colleagues have previously shown that the F-actin contents of bone marrow and peripheral blood PMN are similar (34). The present studies suggested that IL-6 treatment either increases the F-actin content of PMN in the marrow or accelerates the assembly of F-actin from G-actin. The observation that the F-actin increase following FMLP activation of PMN was similar in both the IL-6 and control groups (Figures 5A and 5B) suggests that IL-6 does not accelerate the conversion of G-actin to F-actin but rather increases the total amount of F-actin in PMN released from the marrow. Furthermore, the similar distribution of F-actin in PMN at baseline and following FMLP stimulation in IL-6-treated and control groups (Figure 6) supports the concept that IL-6 does not activate PMN but releases PMN from the marrow with higher levels of F-actin.
Our filtration studies show that IL-6 treatment decreases the deformability of circulating PMN (Figure 8), and we postulate that the increase in F-actin content of PMN induced by IL-6 treatment (Figure 5) is responsible for this change in PMN deformability. Several workers (12, 13) have shown F-actin assembly during cell activation with the redistribution of F-actin to the cell periphery where it plays a key role in reducing cell deformability. The immunofluorescent studies show no redistribution of F-actin in circulating PMN of IL-6-treated animals (Figure 6) supporting the notion that the increase in F-actin of these PMN is not due to cell activation. We suspect that this diffuse increase in F-actin of PMN following IL-6 treatment changes their deformability and is responsible for the sequestration of PMN in the lung microvessels (Figures 3 and 4).
Cell adhesion between PMN and endothelium could also contribute to the sequestration of PMN in lung capillaries. The surface cell adhesion molecules L-selectin and CD18/CD11 complex contribute to prolonged sequestration of PMN in lung capillaries (15, 35). IL-6 treatment did not increase surface CD18 (data not shown) or decrease L-selectin (data not shown) on circulating PMN, suggesting that an increase in PMN adhesiveness is not responsible for the sequestration of PMN in the lung. However, we cannot exclude the possibilities that PMN with enhanced adhesiveness are trapped in the microvascular bed and are not available for sampling in the circulation.
Several studies from our laboratory have shown that immature PMN entering the circulation from the bone marrow following stimuli such as acute pneumonia (19), bacteremia (31), endotoxemia (23), and cigarette smoke exposure (36) preferentially sequester in the pulmonary microvessels. Our hypothesis is that activation of the sequestered PMN in the lung microvessels by local or circulating inflammatory mediators could damage the vascular endothelium. The present results suggest that high circulating levels of IL-6 in conditions such as sepsis, ARDS (2), and multiorgan failure (3) could increase the number of PMN sequestered in the microvascular bed but other stimuli are required to activate the cells to contribute to tissue damage and organ dysfunction.
In summary, the data presented here show that IL-6 induces an accelerated release of younger less mature PMN into the circulation and these younger PMN preferentially sequester in the lung microvessels. These PMN also have high levels of F-actin and are less deformable suggesting that these functional characteristics are responsible for their sequestration in the lung. We speculate that the newly released PMN could play an important role in injuring the capillary endothelium, if they were activated during their prolonged transit through lung capillaries.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Stephan F. van Eeden, M.D., Pulmonary Research Laboratory, University of British Columbia, St. Paul's Hospital, 1081 Burrard street, Vancouver, BC, V6Z1Y6 Canada. E-mail: svaneeden{at}mrl.ubc.ca
(Received in original form May 31, 2000 and in revised form September 7, 2000).
Acknowledgments: Dr. S. F. van Eeden is a recipient of a Career Investigators Award from the American Lung Association. The authors thank Beth Whalen, Dean English, and Diane Minshall for technical supports and Stuart Greene for photography.
This work was supported by a grant from the Medical Research Council of Canada (Grant 4219) and the Toxic Substance Research Initiative.
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References |
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INTRODUCTION
METHODS
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DISCUSSION
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