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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
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The C-C chemokine monocyte chemotactic protein 1 (JE/MCP-1) is
a key cytokine for lung monocyte recruitment, and may be detected in high levels in the alveolar space in lung injury. We hypothesized that alveolar JE/MCP-1 might synergize with endotoxin in this compartment to elicit lung inflammatory events.
Intratracheal instillation of JE/MCP-1 into BALB/c mice did not
provoke increased bronchoalveolar lavage tumor necrosis factor 
(TNF-), interleukin 6 (IL-6), and macrophage inflammatory protein 2 (MIP-2) levels, but elicited monocyte recruitment into this
compartment. Intratracheal Escherichia coli endotoxin provoked elevated lavage TNF-, IL-6, and MIP-2 levels, peaking after 6 h in
parallel with increased alveolar neutrophil numbers, in the absence of vascular leakage. Mice receiving both endotoxin and JE/
MCP-1 showed drastically increased lavage TNF-, IL-6, and MIP-2
levels, 22-fold higher lavage neutrophil numbers, and lung vascular leakage. Moreover, an 8-fold increased alveolar accumulation
of monocytes, peaking at 48 h together with expansion of the resident alveolar macrophage pool, was noted. Intraperitoneal instead of alveolar deposition of MCP-1 or endotoxin failed to reproduce the synergistic response, and the same was true for
employment of RANTES instead of MCP-1. Blockade of neutrophil
recruitment by anti-CD18 did not affect the intra-alveolar cytokine
response to MCP-1 plus endotoxin. Together, JE/MCP-1 and endotoxin, when coappearing in the alveolar compartment at low
dosage, elicit an early phase of lung inflammatory injury with increased cytokine synthesis and neutrophil recruitment, and a late
phase of enhanced monocyte traffic and expansion of the alveolar
macrophage pool.
Keywords: lung; cytokine; alveolar monocyte; inflammation
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Monocyte chemotactic protein 1 (MCP-1) is a glycoprotein of
76 amino acids and belongs to the C-C family of chemotactic
factors. MCP-1 is produced in response to inflammatory stimuli such as interleukin 1
(IL-1) and tumor necrosis factor (TNF-) by various cell types, including monocytes, macrophages, and endothelial cells of various organ sources, alveolar type I and type II epithelial cells, fibroblasts, and smooth
muscle cells (1). Various transgenic mouse models have revealed a causal relationship between MCP-1 expression and
monocyte recruitment into several organs, such as the pancreatic islets, the brain, the skin, or the lung (4). Moreover, enhanced MCP-1-driven monocyte accumulation has been implicated in a number of acute and chronic inflammatory diseases, such as atherosclerosis (2, 8), glomerulonephritis (12, 13),
diabetes (5), and respiratory failure (14). Concerning the
lung, elevated bronchoalveolar lavage (BAL) fluid levels of MCP-1 were noted to parallel increased numbers of monocytes recruited into the alveolar space and to be correlated
with poor outcome in patients with acute respiratory distress
syndrome of septic origin (14).
So far, the pathogenetic relevance of MCP-1 in lung disease has thus mainly been attributed to the enhancement of
monocyte recruitment. In addition to its potent monocyte chemoattractant activities, MCP-1 has also been reported to modulate monocyte-macrophage effector cell functions, for example, by enhancing 2-integrin expression (17, 18), which is
known to be important for monocyte passage across the endo-
and epithelial barrier both in vitro and in vivo (19, 20). However, little is known about any further impact of MCP-1, when,
for example, arising in the alveolar space, on lung inflammatory events such as those elicited by lipopolysaccharides (endotoxin) as a prototype microbial product. In the present
study, we used a mouse model that permits the identification
and quantification of monocytes recruited into the alveolar
space, next to resident alveolar macrophages and neutrophils,
in companion with the use of tools for molecular analysis (21).
We questioned whether JE/MCP-1, introduced into the alveolar space, might synergize with endotoxin to enhance both
neutrophil and monocyte traffic into this compartment, and
whether this is related to an upregulation of the inflammatory
response and lung vascular injury.
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INTRODUCTION
METHODS
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DISCUSSION
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Animals
BALB/c female mice (18-21 g) were purchased from Charles River (Sulzfeld, Germany) and used in all experiments.
Reagents
The red fluorescent dye PKH26-PCL and diluent B solution were purchased from Zynaxis (Malvern, CA) or Sigma (Deisenhofen, Germany). Murine JE, the homolog to the human MCP-1 gene product (22), was purchased as a recombinant protein preparation from R&D Systems (Wiesbaden, Germany), as was recombinant RANTES. All reagents and monoclonal antibodies (MAbs) were ascertained to be endotoxin free by Limulus amebocyte lysate (LAL) assay (COATEST, Chromogenix, Mölndal, Sweden; detection limit < 10 pg/ml).
Antibodies
Hybridoma producing function-blocking anti-murine CD18 antibody (2E6; isotype IgG2a) has been described (23) and was obtained from the American Type Culture Collection (ATCC, Rockville, MD). Nonimmune hamster IgG was used as control (Sigma). For inhibition experiments mice received intravenous injections of 100 µg of MAb in a volume of 100 µl via the tail vein, followed by intratracheal instillation of the respective reagents. Rat anti-mouse antibody F4/80 and fluorescein isothiocyanate (FITC)-conjugated goat anti-rat F(ab)2 were obtained from Serotec (München, Germany).
Treatment of Animals and Treatment Protocol
In vivo fluorescent labeling of resident alveolar macrophages was performed as described (21).
Three treatment groups were evaluated: (1) mice receiving JE/ MCP-1 in the absence of E. coli endotoxin, (2) mice receiving E. coli endotoxin in the absence of JE/MCP-1, and (3) mice receiving endotoxin plus JE/MCP-1. Control mice received PKH intravenously and intratracheal instillations of sterile PBS/0.1% human serum albumin (HSA). Twenty-four hours after intravenous injection of PKH26, BALB/c mice were anesthetized and murine rJE/MCP-1 (50 µg/mouse), Escherichia coli endotoxin (10 ng/mouse) or JE/MCP-1 plus E. coli endotoxin was instilled intratracheally as described (21).
Effect of Anti-CD18 on Alveolar Leukocyte Emigration and
Lavage Fluid TNF- and MIP-2 Levels
Mice were pretreated with anti-CD18 (2E6; 100 µg /mouse) followed by tracheal instillation of E. coli endotoxin (10 ng) plus JE/MCP-1 (50 µg). After 6 h, BAL was performed, total cell numbers were counted, and BAL fluid cytokines were analyzed by enzyme-linked immunosorbent assay (ELISA).
Lung Permeability Assay
Lung permeability was analyzed as described (24). Undiluted BAL fluid and serum samples (diluted 1:10 and 1:100 in PBS, pH 7.4) were measured with a fluorescence spectrometer (FL 600; Bio-Tek, Winooski, VT) at an absorbance wavelength of 488 nm and an emission wavelength of 520 (± 20) nm. The lung permeability index is defined as the ratio of fluorescence signals of undiluted BAL fluid samples to fluorescence signals of 1:100 diluted serum samples.
Collection of Blood Samples and Bronchoalveolar Lavage
At various time points, mice of different experimental groups (n = 4- 6 each) were killed and blood samples and BAL fluid were collected. Serum was recovered by centrifugation (2,500 rpm) at 25° C for 10 min. BAL and determination of total cell counts were performed as described (21).
Flow Cytometry
A FACStarPLUS flow cytometer (Becton Dickinson, San Jose, CA) was used throughout the study (25). Identification of alveolar recruited leukocytes was performed as described (21, 26, 27).
Ribonuclease Protection Assay
Quantitation of JE/MCP-1 and MIP-2 mRNA transcripts was performed by ribonuclease protection assay (RPA), according to the manufacturer instructions (Chomczynski and Sacchi [28]; PharMingen, Carlsbad, CA).
ELISA
Quantitation of BAL fluid TNF-, IL-6, and MIP-2 protein levels
was performed with commercial ELISA kits (R&D Systems, Minneapolis, MN).
Statistics
Data are given as means ± SEM. Statistical significance between treatment groups was estimated by Mann-Whitney U test. Differences were assumed to be statistically significant when p values were less than 0.05.
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RESULTS |
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Effect of Intratracheal Instillation of JE/MCP-1, Escherichia coli Endotoxin, or Escherichia coli Endotoxin plus JE/MCP-1 on BAL Fluid Cytokine Levels
Intratracheal instillation of JE/MCP-1 in the absence of endotoxin did not induce detectable quantities of TNF-, IL-6,
or MIP-2 in the lavage fluid, as shown in Figure 1A-1C. BAL
fluids collected from mice that received 10 ng of intratracheal
E. coli endotoxin in the absence of JE/MCP-1 contained
slightly elevated TNF-, IL-6, and MIP-2 protein levels, with
values peaking at 6 h and subsequently rapidly declining,
reaching baseline values at 12 h postinstillation. Simultaneous
intratracheal instillation of E. coli endotoxin and JE/MCP-1
provoked drastically increased TNF-, IL-6, and MIP-2 BAL
fluid cytokine levels that again peaked at 6 h and returned to
baseline values by 12-24 h. This cytokine response to coadministration of JE/MCP-1 and endotoxin was much less prominent (peak values < 30%) in animals, in which the standard E. coli endotoxin dose was combined with JE/MCP-1 at 10 µg/
mouse (data not shown in detail). It is noteworthy that no IL-10
protein was detectable in BAL fluids of either treatment
group, irrespective of the time point analyzed.
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We also studied the time course of JE/MCP-1 and MIP-2 gene expression in the lungs of mice that were treated either with JE/MCP-1, E. coli endotoxin, or both agents. Instillation of JE/MCP-1 alone did not induce detectable JE/MCP-1 or MIP-2 mRNA levels (data not shown). Instillation of E. coli endotoxin slightly increased both JE/MCP-1 (0.25 ± 0.03 AU; means ± SEM; p < 0.05 versus treatment with exogenous JE/ MCP-1; n = 3) and MIP-2 gene expression (0.17 ± 0.05; p < 0.05 versus JE/MCP-1 treatment; n = 3) by 6 h, which returned to near baseline levels by 72 h. Simultaneous treatment of mice with E. coli endotoxin and JE/MCP-1 further increased JE/MCP-1 and MIP-2 gene expression to peak levels observed at 6 h (JE/MCP-1, 0.7 ± 0.06 AU; MIP-2, 0.4 ± 0.05 AU; both p < 0.05 versus sole endotoxin treatment), again returning to near baseline levels by 72 h.
Effect of Intratracheal Instillation of JE/MCP-1, Escherichia coli Endotoxin, or Escherichia coli Endotoxin plus JE/MCP-1 on Bronchoalveolar Lavage Fluid Neutrophil and Monocyte Accumulation
The time course of alveolar neutrophil and monocyte accumulation in response to treatment with either intratracheal JE/ MCP-1, E. coli endotoxin, or E. coli endotoxin plus JE/MCP-1 is summarized in Figure 2. Treatment of mice with only JE/ MCP-1 elicited a monocyte but not a neutrophil influx into the bronchoalveolar compartment, with BAL fluid monocyte numbers peaking at 48 h (Figure 2A-2C). Intratracheal instillation of low doses of E. coli endotoxin time dependently elicited neutrophils (PMNs) but not monocyte accumulation in the alveolar space, with BAL fluid neutrophil counts displaying peak values at 12-24 h, and subsequent declining to near baseline values by 72 h (Figures 2A and 3A). Under these conditions, no expansion of the resident alveolar macrophage pool was observed (Figure 2C). However, when mice were challenged with endotoxin in the presence of JE/MCP-1, we observed a drastically increased alveolar accumulation of both neutrophils and monocytes, yet with different kinetics: 22-fold increased neutrophil counts were detected 12 h after this dual challenge, as compared with mono-endotoxin treatment (p < 0.05), returning to near baseline values by 72 h (Figures 2A and 3B). Monocyte numbers started to increase 6 to 12 h after JE/MCP-1/ endotoxin administration, with peak values observed at 48 h, corresponding to an 8-fold increase of lavage monocyte counts compared with mono-JE/MCP-1-treated animals (p < 0.05). Subsequently, as observed for PMNs, monocyte counts declined but did not fully reach baseline values at 72 h posttreatment (Figures 2B and 3B). Interestingly, the increased alveolar recruitment of monocytes in lipopolysaccharide (LPS)/JE/ MCP-1-treated mice was paralleled by a significant expansion of the resident alveolar macrophage pool, with resident alveolar macrophage (rAM) numbers peaking at 48 h, suggesting a rapid monocyte-to-macrophage transition under these conditions. As described for PMNs and monocytes, rAM counts then declined, but did not fully approach baseline values at 72 h.
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Effect of Anti-murine CD18 Monoclonal Antibodies on
Alveolar Leukocyte Emigration and Lavage Fluid TNF-
and MIP-2 Levels
We analyzed, whether peak BAL fluid cytokine levels observed in mice at 6 h posttreatment were due to the compartmentalized alveolar inflammatory response provoked by intratracheal injection of E. coli endotoxin plus JE/MCP-1, or
provoked by an increased alveolar accumulation of neutrophils. Pretreatment of mice with anti-murine CD18 Ab followed by intratracheal E. coli endotoxin plus JE/MCP-1 decreased BAL fluid leukocyte counts by 68% [E. coli endotoxin + JE/MCP-1, 1.3 (± 0.1) × 106, versus E. coli endotoxin + JE/
MCP-1 + anti-CD18, 4.2 (± 0.4) × 105; mean ± SEM, n = 4].
FACS analysis as well as cytologic differentiation of Pappenheim-stained BAL cell aliquots revealed > 96% rAMs and < 3% neutrophils, respectively. In spite of this marked suppression of neutrophil influx, analysis of BAL fluid cytokine levels
of CD18-pretreated mice showed that TNF- protein was
slightly but nonsignificantly decreased compared with E. coli
endotoxin plus JE/MCP-1-treated mice, and no differences
between treatment groups were observed with respect to BAL
MIP-2 levels (Figure 4), suggesting that peak cytokine levels
observed at 6 h posttreatment of mice with E. coli endotoxin
plus JE/MCP-1 were largely independent of the alveolar recruitment of neutrophils peaking at the same time point.
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Effect of Low JE/MCP-1 Dosage and RANTES Being Coapplied with Escherichia coli Endotoxin
Coadministration of a low JE/MCP-1 dose (10 µg/mouse) with the standard E. coli endotoxin dose was compared with the above-described combination of endotoxin with JE/MCP-1 at 50 µg/mouse (Figure 5). A significantly lower alveolar accumulation of both neutrophils, evaluated at 12 h, and monocytes, evaluated 48 h posttreatment, was noted (p < 0.05 for both leukocyte types). When tracheal instillation of E. coli endotoxin was combined with RANTES (regulated on activation, normal T cell expressed and secreted; 50 µg/mouse) rather than JE/MCP-1, no monocyte recruitment was detected (data not shown).
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Effect of Intratracheal Instillation of JE/MCP-1, Escherichia coli Endotoxin, or Escherichia coli Endotoxin plus JE/MCP-1 on Lung Permeability
Because of the finding that intratracheal instillation of E. coli endotoxin plus JE/MCP-1 significantly increased BAL fluid cytokine levels, in companion with elevated intrapulmonary PMN and monocyte accumulation as compared with sole endotoxin treatment, we questioned whether this inflammatory response was associated with increased lung permeability. Treatment of BALB/c mice with intratracheal E. coli endo-toxin alone did not increase lung permeability above values observed in control mice receiving intravenous PKH26 and intratracheal instillation of PBS-0.1% HSA, irrespective of the time point analyzed (Figure 6). In contrast, treatment of mice with E. coli endotoxin plus JE/MCP-1 significantly increased lung protein leakage at 6 h, with peak values reached 12 h posttreatment (p < 0.05 versus endotoxin treatment and control). At 48 h, lung permeability was only moderately increased as compared with controls, and it reached near baseline values at 72 h (Figure 6).
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DISCUSSION
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In the present study in mice, the intratracheal instillation of the C-C chemokine JE/MCP-1 provoked a delayed monocyte influx into the alveolar compartment, with a climax after 48 h, without enhanced neutrophil traffic or upregulation of proinflammatory cytokines being detectable. In contrast, introduction of low doses of endotoxin into the bronchoalveolar space elicited an early neutrophilic response, with lavage numbers of this leukocyte type peaking after 6 h, accompanied by a moderate upregulation of lung proinflammatory cytokine synthesis. Most impressively, a dramatic amplification of both the PMN and the monocyte recruitment response, again with biphasic kinetics, and the upregulation of proinflammatory cytokines was noted on coadministration of MCP-1 and endotoxin into the bronchoalveolar compartment. In addition, increased lung vascular leakage, occurring in parallel with the neutrophil but not the monocyte influx, was noted under these conditions. The monocyte accumulation was mirrored by an expansion of the resident alveolar macrophage pool. All events were found to be reversible, with near baseline levels being reached again after 72 h.
As anticipated from the basic features of this C-C chemokine, bronchoalveolar JE/MCP-1 provoked a well-detectable monocyte influx into this compartment, without any change in lavage neutrophil numbers, lung proinflammatory cytokine synthesis, or vascular macromolecular barrier properties being noted. Similarly, no upregulation of pulmonary JE/MCP-1 or MIP-2 mRNA levels was observed in response to the challenge with exogenous JE/MCP-1. This observation is consistent with the previous notion that significant lung monocyte recruitment is not necessarily accompanied by lung inflammatory injury (6).
In contrast to JE/MCP-1, bronchoalveolar endotoxin deposition provoked sole neutrophil influx into this compartment,
which in addition occurred with more rapid kinetics as compared with the monocytes. Moreover, some additional upregulation of lung proinflammatory cytokine and chemokine synthesis was noted in response to lipopolysaccharide, including
TNF- and IL-6 as well as MIP-2 and JE/MCP-1, whereas no
upregulation of the antiinflammatory IL-10 was observed. Interestingly, most endotoxin-elicited events peaked after 6 h,
with return to near baseline values only 6 h later. At the given
dose, the limited lung inflammatory response to endotoxin
was not linked with significant vascular leakage. This finding is
well in line with previous studies, demonstrating inflammatory
sequelae in the lung tissue in response to alveolar endotoxin in
the absence of readily detectable abnormalities of lung physiology (29).
Most dramatic changes were, however, encountered on alveolar coadministration of JE/MCP-1 and the low endotoxin dose presently employed, and this was true for all changes monitored: the neutrophil influx increased ~ 22-fold and the monocyte influx ~ 8-fold as compared with the respective monostimuli, and a manifold increase was also noted for lung proinflammatory cytokine synthesis. Interestingly, this dramatic amplification of responsiveness did not alter the distinct time courses of events, with climaxes of cytokines and PMNs still at 6-12 h, and alveolar monocytes peaking at 48 h. Moreover, vascular leakage became detectable under these conditions, and this clearly paralleled the early neutrophilic/proinflammatory cytokine response, but not the late monocyte response, which again sets the monocyte influx apart from serious lung damage in this model. Concerning neutrophils, in contrast, there is a large body of experimental data demonstrating that enhanced recruitment and activation of this leukocyte type may promote severe lung vascular injury (29).
The mechanism(s) underlying this impressive synergism of
alveolar JE/MCP-1 and endotoxin in eliciting inflammatory
lung events largely remain to be elucidated. Concerning the
early phase of response, characterized by neutrophil influx,
cytokine upregulation, and vascular leakage, the amplification
may not be attributed to co-migrating monocytes, as such migration was clearly delayed. The amplified response in this
early period was, however, apparently dependent on the type
of chemokine involved, as it was not mimicked by coapplication of endotoxin and RANTES, another C-C chemokine with
known monocyte chemoattractant activities (32). Moreover, alveolar deposition of both MCP-1 and endotoxin was a prerequisite for the response: intraperitoneal injection of either
agent, with alveolar deposition of the respective other agent,
did not reproduce the synergism in eliciting a lung inflammatory response, but even some reverse effect was noted (data
not shown). These topic requirements of the MCP-1/endotoxin
synergism may explain why Zisman and coworkers did not notice enhanced lung injury on intraperitoneal administration of
MCP-1 and intravenous application of endotoxin (33). Finally, the enhancement of neutrophil traffic in the early period after alveolar coapplication of endotoxin and MCP-1 may per se
not explain the upregulation of proinflammatory cytokines, as
anti-CD18-mediated blockade of neutrophil invasion did not
substantially change the cytokine response. Thus, resident cells
of the alveolar compartment, such as alveolar macrophages
and/or type II alveolar epithelial cells, which are both known
to be responsive to endotoxin and TNF- or IL-1 for increased MCP-1 production (1, 3, 34), may be suggested to be
the primary targets of these coapplied agents, possibly acting
in a cooperative fashion but independent of the (later) invading neutrophils and monocytes, to trigger inflammatory events,
which then also include enhanced PMN and monocyte traffic.
Interestingly, the manifold increased leukocyte numbers accumulating in the alveolar space on coadministration of JE/MCP-1 and endotoxin rapidly declined to near baseline within 72 h posttreatment. Neutrophils demonstrated significant signs of apoptosis already within 24 h, as analyzed by TUNEL assay in pilot experiments (data not shown). Concerning the monocytes, this cell type is assumed to expand the alveolar macrophage pool, a notion compatible with the time course of increase in rAM numbers. However, even the alveolar macrophages were found to undergo subsequent rapid decline in numbers, again suggesting rapidly commencing apoptotic events. Thus, as the inflammatory stimulus according to our protocol did not persist over a longer time period, self-limitation of the inflammatory sequelae apparently occurred, with all abnormalities approaching baseline values within 72 h.
In conclusion, the presence of JE/MCP-1 and endotoxin in the alveolar compartment synergize to cause a dramatically enhanced lung inflammatory response. This includes an early phase with upregulation of inflammatory cytokines in the lung tissue, neutrophil invasion into the alveolar compartment, and increased lung vascular leakage. A later phase is characterized by marked monocyte flux into the alveolar space and expansion of the alveolar macrophage pool. Coappearance of MCP-1 and endotoxin in the alveolar space, which may well occur under pathophysiological conditions of infection or inflammation, may thus give way to severe lung inflammatory injury not anticipated from the efficacy profile of each single agent.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Ulrich A. Maus, Ph.D., Department of Internal Medicine, Justus-Liebig-University, Klinikstrasse 36, Giessen 35392, Germany. E-mail: Ulrich.A.Maus{at}med.uni-giessen.de
(Received in original form September 25, 2000 and in revised form March 7, 2001).
This article includes part of the thesis of J. Huwe.Acknowledgments: The authors thank G. Mansouri and M. Lohmeyer for excellent technical assistance.
Supported by the Deutsche Forschungsgemeinschaft, grant SFB 547 (Cardiopulmonary Vascular System).
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