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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Eosinophilia is a feature of airway inflammation associated with
asthma. Leukotriene antagonists provide therapeutic benefit in
asthma, but their potential antiinflammatory actions have not been fully explored. We have examined the role of eosinophil-derived cysteinyl leukotrienes in the maintenance of eosinophil survival, and the involvement of leukotrienes in the paracrine stimulation of eosinophil survival by mast cells and lymphocytes. We
obtained eosinophils and autologous lymphocytes from peripheral
blood of asthmatic subjects. Leukotriene (LT)-B4, LTC4 and LTD4,
granulocyte-macrophage colony-stimulating factor (GM-CSF),
and fibronectin promoted eosinophil survival. LTD4 (10
6 M) was
as effective as GM-CSF (5 ng/ml) and fibronectin (400 ng/ml) in
promoting survival. Lymphocytes and conditioned medium from a
human mast cell line (HMC-1) induced eosinophil survival. Blockade of cysteinyl leukotriene receptors with SKF 104353 (pobilukast, 3 nM), and inhibition of 5-lipoxygenase (5-LO) with BW
A4C (1 µM) and of 5-LO activating protein with MK 886 (1 µM), all
increased basal rates of eosinophil apoptosis and reversed GM-CSF-induced eosinophil survival. Fifty percent reversal of GM-CSF-
induced survival was achieved with SKF 104353 at 0.3 nM. The potency of SKF 104353 was two orders of magnitude greater than
that of the LTB4 receptor antagonist SB 201146. Mast cell- and
lymphocyte-induced eosinophil survival were completely reversed
by SB 201146, SKF 104353, BW A4C, and MK 886. These findings
provide evidence for the involvement of an autocrine cysteinyl leukotriene pathway that supports eosinophil survival in response to
a range of survival stimuli. They also suggest that LTB4 could act as
a paracrine stimulus of eosinophil survival.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Leukotrienes are involved in leukocyte chemotaxis, tissue edema, mucus secretion, and smooth-muscle proliferation and bronchoconstriction. These properties have provided a rationale for the clinical development of leukotriene synthesis inhibitors and selective leukotriene receptor antagonists for treating of asthma. This class of compounds demonstrates a steroid-sparing action in asthma (1) and reduces the number of exacerbations in asthmatic individuals during corticosteroid reduction regimens (2). These findings indicate an antiinflammatory activity of leukotriene inhibitors, but this has not been fully explored.
Eosinophil products, including cysteinyl leukotrienes, could contribute to airway inflammation in asthma (3). Cysteinyl leukotrienes facilitate bronchoconstriction, and could also be involved in eosinophil survival. Eosinophils and neutrophils undergo spontaneous apoptosis and are subsequently engulfed by macrophages. This action of macrophages prevents progression of granulocyte apoptosis to necrosis, and provides a noninflammatory route for the resolution of granulocyte- mediated inflammation (4). The present study examined the potential for leukotrienes and leukotriene inhibitors to influence eosinophil survival. Granulocyte-macrophage-colony stimulating factor (GM-CSF) maintains the survival of neutrophils, eosinophils, monocytes, and macrophages. The survival signaling induced by GM-CSF could involve increased leukotriene production by these cells. Exposure of neutrophils to GM-CSF results in increased 5-lipoxygenase (5-LO) activity and leukotriene production (5). Furthermore, we have previously shown that an autocrine pathway involving leukotriene (LT)-B4 contributes to neutrophil survival induced by GM-CSF and lipopolysaccharide (LPS) (6).
Eosinophil survival is also promoted by adhesion. Eosinophil migration into inflammatory sites involves an interaction between the integrin very late antigen (VLA)-4 and vascular cell adhesion molecule (VCAM)-1 on eosinophils. The interaction between eosinophil VLA-4 and VCAM-1 on fibronectin induces eosinophil survival (7). This action appears to be mediated by release of GM-CSF (8). The VCAM-1/eosinophil VLA-4 interaction also results in eosinophil leukotriene production (9, 10), which could be a consequence of GM-CSF release (7). In addition to their generation by eosinophils, mast cells and T-helper type 2 (Th2) lymphocytes also generate interleukin (IL)-5 and GM-CSF, and could thereby promote eosinophil survival. Mast cells and lymphocytes also produce leukotrienes, which through activation of eosinophils could thereby influence the latters' survival.
This study examined the role of leukotrienes in the maintenance of eosinophil survival under conditions of stimulation by GM-CSF, VCAM-1 adhesion, mast cells, and lymphocytes. The findings indicate that cysteinyl leukotrienes mediate survival signals carried by GM-CSF and the interaction between fibronectin-derived VLA-4 and VCAM-1. The findings also indicate the involvement of leukotrienes in maintenance of eosinophil survival in response to paracrine signals from the mast cell and lymphocyte. Furthermore, the findings of the study imply that inhibition of eosinophil survival could provide an additional mode of action of leukotriene receptor antagonists and leukotriene synthesis inhibitors in the treatment of asthma.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Materials
All reagents, except where stated, were obtained from Sigma, Poole, UK. SB 201146 and SKF 104353 were provided by Dr. D. Hay of Smithkline Beecham, King of Prussia, PA. BW A4C was provided by Dr. L. Garland of the Wellcome Research Laboratories, Beckenham, Kent, UK. MK 886 was obtained from Tocris, Bristol, UK.
Subjects
All subjects had atopic asthma and exhibited skin responses to at least
one common allergen, as well as having circulating eosinophilia and
reversibility of airway constriction with a > 15% increase in FEV1
in response to 
2-agonists. The age of subjects was 40.6 ± 5.0 yr (mean ± SE) (range: 19 to 65 yr). Subjects were mild to moderate asthmatics. The subjects FEV1 % predicted was 85.6 ± 3.2 (range: 68 to 100).
All were taking inhaled corticosteroids (400 to 2,000 µg beclomethasone dipropionate or equivalent), and no leukotriene receptor antagonists or other treatments for asthma. All subjects had been free of
airway infection for at least 6 wk before investigation.
Isolation of Eosinophils
Unless stated, procedures up to and including density-gradient centrifugation were conducted at 22° C. Anticoagulated (acid-citrate- dextrose) blood was centrifuged at 400 × g for 20 min to remove platelets. The platelet-rich plasma was separated from the leukocytes and centrifuged at 2,000 × g for 30 min to prepare platelet-poor plasma (PPP). Platelet-depleted leukocytes and erythrocytes from the first centrifugation were mixed with phosphate-buffered saline (PBS) without magnesium and calcium. Dextran (Baxter, Warrington, UK) was added to a final concentration of 2%, and the suspension was left to stand for 45 min at 15° C. The leukocyte-enriched supernatant produced from erythrocyte sedimentation was centrifuged at 400 × g for 10 min. The pellet was resuspended with 4 ml of autologous PPP and layered over 61.5% and 76% Percoll gradients. The Percoll was made from pure Percoll by dilutions using PPP and PBS (10×). Final percentages of PPP (vol/vol) in the Percoll solution were 42.89% and 23.97% for the 61.5% and 76.0% Percoll layers, respectively. The leukocytes with the layered Percoll were centrifuged at 400 × g for 20 min. The mononuclear cells were removed from the PPP-61.5% Percoll-layer interface, and the granulocytes were removed from the 61.5%-76% Percoll-layer interface. Granulocytes were washed twice in RPMI-1640 with centrifugation at 400 × g for 10 min, and were counted with a hemocytometer. The granulocytes were mixed with anti-CD-16-coated magnetic beads (Macbeads; Miltenyi Biotec Ltd, Bisley, UK) (1 µl of beads per 106 cells) and left at 4° C for 1 h for the binding of magnetic beads to neutrophils. The granulocytes were resuspended in 5 ml of PBS containing 0.02% ethylenediamine tetraacetic acid (EDTA) and 0.01% bovine serum albumin and passed through an E-mac column and magnet (Variomax) to retain the CD16-attached neutrophils. The eosinophils were collected from the column and washed twice with centrifugation at 400 × g for 10 min in PBS containing 0.02% EDTA, and were then resuspended in RPMI-1640. Lymphocytes were obtained from the mononuclear cells by incubation for 1 h on a plate not treated for tissue culture. Lymphocytes were removed, leaving adherent monocytes on the plate, and were washed for 10 min with RPMI-1640 followed by centrifugation at 400 × g. Human mast cell culture supernatant was obtained from cells of the human mast cell line HMC-1 in the absence of leukotriene inhibitors.
Incubation of Eosinophils with GM-CSF and Fibronectin
Eosinophils were plated in a 96-well tissue culture plate (80,000 eosinophils/well). Basal eosinophil apoptosis rates were determined under culture conditions identical to those used to determine the response to other agents. GM-CSF and fibronectin were therefore absent under basal conditions. The concentrations of leukotriene receptor antagonists and leukotriene synthesis inhibitors used were those providing a maximal or near-maximal effect on concentration-effect curves established in a previous study with neutrophils (6). Leukotriene receptor antagonists and leukotriene synthesis inhibitors included SB 201146 (an LTB4 receptor antagonist [10 pM to 1 µM]) and SKF 104353 (an LTC/ D4 receptor antagonist [10 pM to 1 µM]); BW 4AC (a 5-lipoxygenase [5-LO] inhibitor [1 µM]), and MK 866 (a 5-LO activating-protein [FLAP] inhibitor [0.3 µM]). Compounds used to activate eosinophils (GM-CSF [5 ng/ml] and fibronectin [400 ng/ml]) were added 60 min after the leukotriene inhibitors. The eosinophils and tested compounds were incubated in a humidified incubator in a 95% air/5% CO2 atmosphere at 37° C for 40 h. At the end of incubation, the cells were cytospun at 80 × g for 10 min for assessment of apoptosis.
Incubation of Eosinophils with HMC-1 Cells and Lymphocytes
Either 2.4 × 105 lymphocytes or HMC-1-conditioned medium (25% final volume) were added to eosinophils. Leukotriene inhibitors were added to eosinophils 60 min before incubation with either HMC-1 supernatant or lymphocytes. HMC-1-conditioned medium was recovered from HMC-1 cells maintained in Iscove's medium for 7 d.
Assessment of Apoptosis
The degree of apoptosis was assessed from nuclear morphology under oil-immersion light microscopy at a magnification of ×1,000 with a Nikon Eclipse 400 microscope after Giemsa staining. All measurements of apoptosis were made by one observer in a blinded fashion after coding of cytospin preparations by another operator. Apoptotic cells were identified by condensation of the nucleus from a bilobed to a single, densely staining nucleus, or by complete loss of the nucleus. This technique has been validated for neutrophils in a previous investigation by our group, through the demonstration of consistency among measurements of apoptosis made with light microscopy, flow cytometry, and electron microscopy (6). We used eosinophils in the present investigation, and extended the validation by measuring both morphologic changes and flow cytometric features in some of our assessments.
Flow-Cytometric Analysis
Eosinophils were stained through single labeling with annexin V to detect apoptosis. Stained cells were examined with Cellquest software on a FACscan flow cytometer (Beckton Dickinson, Oxford, UK). In flow-cytometric analysis with annexin V staining, two regions of fluorescence were observed under basal conditions, demonstrating distinct populations of eosinophils exhibiting discrete densities of cell-surface phosphatidylserine. A high level of annexin V fluorescence indicated a higher level of apoptosis.
Data Analysis
Data for cell apoptosis are expressed as arithmetic mean ± SE. All values of potency or affinity are expressed as geometric means with 95% confidence intervals. Comparisons were made through analysis of variance. A value of p < 0.05 was accepted as indicating a statistically significant difference.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Eosinophils exhibited a basal rate of apoptosis of 45 to 50% apoptosed cells within the total cell population per 40 h (Figure 1).
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Leukotriene Induction of Eosinophil Survival
An experiment was conducted to demonstrate the effect of leukotrienes and GM-CSF on eosinophil survival. LTB4 (1 µM), LTC4 (1 µM), LTD4 (1 µM), and GM-CSF all significantly induced eosinophil survival. LTD4 was as effective as GM-CSF in promoting eosinophil survival (Figure 1).
Leukotriene Involvement in GM-CSF and Fibronectin-Induced Survival
To investigate agents that could potentially undermine GM-CSF-induced eosinophil survival, we used a high submaximal concentration of GM-CSF (5 ng/ml). Inhibition of leukotriene synthesis by inhibitors of 5-LO (BW A4C, 1 µM) and FLAP (MK 886, 0.3 µM) reversed GM-CSF-induced eosinophil survival (Figure 2). The cysteinyl leukotriene antagonist SKF 104353 reversed GM-CSF-induced eosinophil survival in a concentration-dependent manner, and had a biphasic concentration-effect curve (Figure 3). The cysteinyl leukotriene receptor antagonist SKF 104353 (3 nM) was sufficient to reverse GM-CSF-induced eosinophil survival and return it to basal levels. Higher concentrations of SKF 104353 increased eosinophil apoptosis above basal levels (Figure 3). The LTB4 receptor blocker SB 201146 was used to demonstrate the potential for eosinophil-derived LTB4 to mediate an autocrine activity of eosinophil survival. SB 201146 exhibited a much lower potency and efficacy than did SKF 104353 in reversing GM-CSF- induced eosinophil survival (Figure 3). The reversal of GM-CSF-induced eosinophil survival by SKF 104353 was observed both light microscopically and through flow-cytometric analysis of annexin V staining (Figure 4).
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To further examine the involvement of cysteinyl leukotrienes in eosinophil survival, we replaced another stimulant, GM-CSF, with fibronectin (Figure 5). Fibronectin (400 ng/ml) induced eosinophil survival to a similar level as GM-CSF. Antagonism of cysteinyl leukotriene receptors with SKF 104353 reversed fibronectin-induced eosinophil survival (Figure 5).
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Leukotriene Involvement in Mast Cell and Lymphocyte-Induced Survival
To examine the potential involvement of leukotrienes in a paracrine stimulation of eosinophil survival, we used lymphocytes and HMC-1 culture supernatant to stimulate eosinophil survival. Inhibition of cysteinyl leukotriene receptors by SKF 104353 (30 nM) and of LTB4 receptor with SB 201146 (30 nM) reversed lymphocyte and HMC-1-induced eosinophil survival. Furthermore, inhibition of leukotriene synthesis by inhibitors of 5-LO (BW A4C, 1 µM) and FLAP (MK 866, 0.3 µM) reversed HMC-1-induced eosinophil survival (Table 1). BW A4C (1 µM) also reversed lymphocyte-induced eosinophil survival (Table 1).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We examined the involvement of leukotrienes in autocrine and paracrine stimulation of eosinophil survival by GM-CSF, fibronectin, mast cells, and lymphocytes. We found that LTB4, LTC4, and LTD4 all directly increased eosinophil survival. LTD4 increased eosinophil survival to a similar degree as GM-CSF and fibronectin. Blockade of cysteinyl leukotriene receptors with SKF 104353, and inhibition of leukotriene synthesis with BW A4C and MK 886, reduced eosinophil survival under unstimulated conditions and after exposure to GM-CSF and fibronectin. Blockade of LTB4 receptors with SB 201146, however, was relatively ineffective in reversing GM-CSF-induced eosinophil survival. Mast cells and lymphocytes induced eosinophil survival to a similar degree as GM-CSF. Blockade of receptors for LTB4 and cysteinyl leukotrienes, and inhibition of leukotriene synthesis, were all effective in reversing the paracrine stimulation of eosinophil survival by mast cells and lymphocytes.
The leukotriene inhibitors used in our study reduced basal unstimulated eosinophil survival rates, suggesting a role of leukotrienes in the maintenance of eosinophil survival in the absence of exogenous stimulation. Other eosinophil-derived factors could support leukotriene production in eosinophils. GM-CSF is a major candidate for this, since previous studies have shown that GM-CSF induces eosinophil survival (11, 12) and stimulates granulocyte leukotriene production (13). Furthermore, apoptosis of peripheral blood-derived eosinophils is accelerated in the absence of GM-CSF (8, 16). The present findings suggest an autocrine role of cysteinyl leukotrienes in the maintenance of GM-CSF-induced eosinophil survival. Furthermore, we showed that eosinophil survival can be enhanced by LTC4, supporting the involvement of LTC4 in an autocrine survival pathway.
Concentrations of SKF 104353 above 3 nM, in the presence of GM-CSF, induced greater apoptosis than observed under unstimulated conditions. Although SKF 104353 at 3 nM reversed GM-CSF-induced eosinophil survival to basal levels, SKF 104353 at this same concentration had no effect on LPS-induced neutrophil survival (6). This demonstrates that SKF 104353 does not induce apoptosis of eosinophils through nonspecific toxicity, since the survival of the closely related neutrophil is relatively unaffected by SKF 104353. This concept is supported by the hydrophilic nature of SKF 104353 and the probability that it interacts primarily with a cysteinyl leukotriene receptor on the eosinophil cell surface. Leukotriene synthesis inhibitors, however, exhibit a lower potency in reversing neutrophil survival than do leukotriene receptor antagonists (6). This reflects the requirement for higher concentrations of leukotriene synthesis inhibitors to inhibit 5-LO and FLAP. In addition, the concentrations of leukotriene inhibitors that were effective in reducing survival (6) in this and previous studies are consistent with an action on 5-LO and FLAP.
We used fibronectin as another mode of stimulation of eosinophil survival. Fibronectin stimulation of eosinophil survival involves an interaction between the CS-1 unit of the adhesion molecule VCAM-1 and the eosinophil integrin VLA-4. In the present study, fibronectin-induced eosinophil survival was reversed by the cysteinyl leukotriene receptor antagonist SKF 104353. This finding indicates that cysteinyl leukotrienes play a part in eosinophil survival in response to distinct survival stimuli. GM-CSF could also be involved in the maintenance of eosinophil survival by fibronectin. Fibronectin-induced eosinophil survival is associated with an increase in GM-CSF production, and is inhibited by removal of GM-CSF (17). The VLA-4/VCAM-1 interaction that mediates fibronectin-eosinophil adhesion is also accompanied by leukotriene release from eosinophils (10), possibly as a consequence of fibronectin-induced GM-CSF release (17).
Inhibition of 5-LO and FLAP was found to reverse both eosinophil and neutrophil survival (6). This indicates that leukotriene synthesis inhibitors are not as cell selective as leukotriene receptor antagonists in inducing granulocyte apoptosis under autocrine signaling conditions. This is not necessarily the case under conditions of the paracrine stimulation of survival involved in exposure to mast cells and lymphocytes. Thus, SB 201146 at 0.3 µM did not affect GM-CSF-induced eosinophil survival, but was able to inhibit mast cell- and lymphocyte-induced eosinophil survival at this concentration. This finding is consistent with mast cell- and lymphocyte-derived LTB4 facilitating eosinophil survival in a paracrine fashion. The present findings show that exogenous application of LTB4 induces eosinophil survival (18). Previous studies have shown that T and B lymphocytes have the capacity to produce LTB4 (19, 20). SB 201146 inhibited mast cell-induced eosinophil survival to a similar extent as SKF 104353, indicating that the amount of LTB4 released by the HMC-1 mast cell line used in these studies is sufficient to enhance eosinophil survival. The 5-LO and FLAP inhibitors were applied to eosinophils alone, and not to the mast cells. Both types of inhibitor were found to inhibit mast cell culture supernatant-induced eosinophil survival. This reveals a leukotriene-mediated autocrine activity that was the same as that needed to support the paracrine stimulation of eosinophil survival by mast cells. A major product of the human mast cell line HMC-1 is 5-hydroxyeicosatetraenoic acid (5-HETE), as well as lower concentrations of LTC4 and LTB4 (21). We therefore cannot exclude a contribution of 5-HETE or other products in mast cell induction of eosinophil survival. Similarly, there is a possibility that GM-CSF released from mast cells or lymphocytes contributes to the maintenance of eosinophil survival.
These findings indicate that LTB4 receptor blockade with SB 201146 does not inhibit autocrine signaling for eosinophil survival, but can inhibit paracrine stimulation of eosinophil survival. This suggests that major LTB4-producing cells, such as neutrophils and macrophages, could maintain eosinophil survival in a manner that is sensitive to LTB4 receptor antagonism.
Corticosteroids induce eosinophil apoptosis in vitro with potencies consistent with the potency of their other antiinflammatory actions in normal and asthmatic subjects (22, 23). Potential direct or indirect effects of inhaled corticosteroids on circulating eosinophil survival have not been established. It is therefore not possible to speculate about the involvement of inhaled corticosteroid administration on the levels of apoptosis obtained in the present study without measurements obtained in the absence of corticosteroid administration.
Our findings are consistent with others that provide evidence for involvement of leukotrienes in the survival of activated inflammatory cells, including the neutrophil (6) and monocyte (unpublished data). These findings suggest the involvement of leukotrienes in survival of several cell types under differing conditions, and therefore possibly in the airways.
These findings also have relevance to the benefit derived from leukotriene receptor antagonists and leukotriene synthesis inhibitors in the treatment of asthma. The clinical efficacy of these compounds has been attributed primarily to inhibition of leukotriene-mediated chemotaxis and bronchoconstriction. The findings in the present study suggest that inhibition of eosinophil survival should also be considered a potential additional mode of action of these drugs. It is noteworthy that leukotriene inhibition reduces the eosinophil content of circulating blood (24) and of sputum (27) and bronchoalveolar lavage fluid (28) after airway allergen challenge. This could be related to an acceleration of eosinophil apoptosis by leukotriene receptor antagonists and synthesis inhibitors.
In conclusion, we found that eosinophil survival is supported by both LTB4 and cysteinyl leukotrienes. Mast cells and lymphocytes also maintain eosinophil survival, and the action of these cells appears to involve leukotrienes. These findings are consistent with the involvement of leukotrienes in the survival of inflammatory cells. They also indicate an additional potential mode of action of cysteinyl leukotriene receptor antagonists in the treatment of asthma.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. Stephen Kilfeather, Institute for Cardiovascular and Respiratory Pharmaceutical Development, School of Sciences, University of Sunderland, Chester Road, Sunderland, SR1 3SD UK. E-mail: stephen.kilfeather{at}sunderland.ac.uk
(Received in original form July 13, 1999 and in revised form November 24, 1999).
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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