 -inhibitor in Experimental Endotoxic
Shock and Disseminated Intravascular Coagulation
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We investigated the effects of human inter-
-inhibitor (II) on hemodynamics, oxygenation, and coagulation parameters in a porcine model of endotoxic shock. Four groups of six animals were studied:
(1) control, (2) II group receiving 30 mg/kg II over 30 min, (3) LPS group receiving 5 µg · kg/min
Escherichia coli endotoxin over 30 min, and (4) LPS + II group receiving 30 min after endotoxin
30 mg/kg/30 min II. We measured hemodynamic and oxygenation parameters, usual coagulation
markers and plasma levels of thrombin-antithrombin complexes, antithrombin III activity, plasminogen activator tissue type, plasminogen activator inhibitor type 1, von Willebrand factor, tumor necrosis factor-, and II at baseline and at 30, 60, 90, 120, 180, 240, and 300 min. In the II group, plasma
II levels reached 447 ± 23 mg/L just after injection and 287 ± 39 mg/L at 300 min. II half-life was
7.3 ± 1.9 h. In the LPS + II group, II plasma levels decreased more rapidly, reaching 260 mg/L at
300 min. Compared with the LPS group, administration of II normalized the mean arterial pressure
and cardiac index, improved the LPS-induced pulmonary hypertension, and resulted in the blunted
increase in blood lactate and oxygen extraction ratio. A significant decrease in thrombin-antithrombin complexes and plasminogen activator inhibitor type 1 levels were observed. There was no significant difference in plasma tumor necrosis factor- levels. We concluded that in this hypodynamic model of endotoxin shock, II administration resulted in a marked improvement in the hemodynamic, oxygenation, and coagulation parameters.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Severe sepsis and septic shock are characterized by hypotension and multiple-organ dysfunction. Substantial evidence supports the concept that mediators involved in this process such as cytokines or eicosanoids induce the activation of phagocytes that release neutrophil proteinases, especially human leukocyte elastase (HLE) (1). The prominent harmful role of HLE is now recognized and indeed its plasma level is in close relation with the severity of infection-induced inflammation and highly predictive of forthcoming organ failure.
Septic shock is frequently associated with an uncontrolled activation of the coagulation and fibrinolytic systems (2) that results in the syndrome of disseminated intravascular coagulation (DIC). DIC is closely linked to the development of the multiple-organ failure syndrome and contributes to the poor prognosis of sepsis. It may be amplified by the neutrophil proteinases able to inactivate antithrombin III (ATIII) and other plasma proteins that normally control these pathways.
Accordingly, among various therapeutic strategies that
have been aimed at reducing DIC in septic shock, administration of human (e.g., ATIII [6] or 1-proteinase inhibitor [7]) or
animal (e.g., aprotinin [8], hirudin [9], or eglin [10]) antiproteinases have been proposed to restore the balance between
proteinases and antiproteinases.
Inter--inhibitor (II), previously named inter--trypsin
inhibitor, is found in human plasma at a concentration of approximately 250 mg/L (11). It consists of one light and two
heavy polypeptide chains covalently linked by a chondroitin-sulfate chain, as recently reviewed by Salier and associates
(12). The light chain, called bikunin, inhibits different serine-proteinases involved in inflammation such as HLE, cathepsin G,
and plasmin (13). Bikunin is also known to exert many other
functions such as inhibition of lymphocyte proliferation (14),
modulation of the release of active oxygen species by polymorphonuclear leukocytes (15), and inhibition of the production and activity of some cytokines: tumor necrosis factor
(TNF) and interleukin (IL)-1, IL-6, and IL-8 (16). Bikunin has been reported to have a beneficial therapeutic effect in
various experimental inflammatory syndromes and has been
proposed in humans as a prophylactic treatment to prevent pancreatitis after gastrectomy (19) or to attenuate multiple-organ
failure after cardiac surgery (20). However, bikunin is quickly
excreted in urine (21), and high doses are needed in order to
obtain a successful effect.
Because of its high molecular mass, II is presumed to
have a longer half-life in plasma. Its proteolysis in inflammatory foci might promote a targeted release of bikunin. Until
now, the functional and metabolic study of II has been severely hindered by the scarcity of the protein. We have recently developed an original procedure for the preparation of
an II concentrate from human plasma (22). The effects of
this molecule have never been studied in septic shock. The
present study was designed to evaluate the effects of human
II administration on both hemodynamics and oxygenation
parameters as well as DIC in a porcine model of endotoxin shock.
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Preparation of Human II
II was isolated as a by-product of a purification scheme designed
to purify coagulation factor IX (LFB, Lille, France; patent number
FR 9312346: attorney docket number 1217-0138PCT), as recently described (22). This procedure includes ion-exchange chromatography and affinity on heparin-Sepharose. The purified product obtained is of
a high-quality grade and revealed no adverse side effects in terms of
toxicity, thrombogenicity, or hypotension.
Animal Preparation
The study was approved by the Institutional Review Board of Animal Research; care and handling of the animals were in accord with National Institute of Health guidelines. The experiments were performed in female piglets weighing 20 to 25 kg. Animals were prepared with an intramuscular injection of 2.5 mg/kg body weight ketamine (Ketalar; Parke-Davis, Courbevoie, France). They were then anesthetized with sodium pentobarbital (10 mg/kg body weight) and midazolam (0.5 mg/kg/min) (Hypnovel; Produits Roche, Neuilly sur Seine, France) and paralyzed with pancuronium bromide (0.5 mg/kg/min) (Pavulon; Organon Teknika, Fresnes, France). The trachea was intubated with a cuffed tube and connected to a constant-volume respirator for mechanical ventilation (ATM Therapair; CFPO, Puteaux, France). After dissection of neck vessels, catheters were inserted in the pulmonary artery via the right external jugular vein and in the left carotid artery for continuous blood pressure monitoring and blood sampling. an esophageal temperature probe measured core temperature, which was maintained near 38° C by heating lamps suspended above the operating table. A standard cardiotachymeter (type 7758B; Hewlett Packard, Palo Alto, CA) was used to monitor the heart rate.
Hemodynamic and Oxygenation Measurements
Cardiac output was measured by thermodilution with a Swan Ganz catheter (Baxter 130 H 7.5F; Baxter Edwards Critical Care, Irvine, CA) (mean of three measurements). Cardiac output was expressed as an index with reference to the body weight and expressed in milliliters per kilogram per minute. Systemic and pulmonary resistances were calculated according to standard formulas. Systemic arterial and venous blood samples from carotid and pulmonary arteries were obtained simultaneously. Arterial and venous blood gas tensions, pH, and hemoglobin saturation were measured in an acid-base and co-oxymeter analyzer at 37° C (ABL-520; Radiometer, Copenhagen, Denmark) and later corrected to esophageal temperature at the time of sampling. The ABL-520 radiometer analyzer directly measures oxygen saturation by spectrophotometry. However, calibration for pig blood is not possible on the ABL-520 radiometer analyzer. For that reason, only oxygen extraction ratio (OER) results are shown and used as relative values. OER was calculated as the difference in the arteriovenous O2 content divided by the arterial O2 content. Carotid lactate levels were determined enzymatically (Hitachi Analyzer 717, BioMérieux kit; Lyon, France).
Experimental Protocol
When all preparations were completed, a 30-min period served to stabilize the measured variables. Measurements were taken over a 5-h period: every 30 min for 2 h and then every hour for 3 h. Arterial and venous blood was sampled at the same time until the protocol was completed.
Four groups were initially studied: control, II, LPS, and LPS + II. Six animals were included in each group. After anesthesia, catheterization, and baseline collection, the control group received an intravenous infusion of 50 ml of isotonic saline over a 30-min period. In
the II group, the same protocol of isotonic saline infusion was used
and then followed at 30 min by the infusion via the central venous line
of 30 mg/kg of human II for 30 min. Human II was dissolved in 80 ml
of sterile water just before administration. In the LPS group, after
catheter placement and baseline data collection, animals were administered 5 mg/kg/min Escherichia coli lipopolysaccharide (LPS) (serotype 055:B5; Sigma Chemical Co., St. Louis, MO). The endotoxin was
diluted in 50 ml of sterile isotonic saline and infused over a 30-min period intravenously. This protocol of porcine endotoxin shock was previously described by Breslow and coworkers (23). In the LPS + II
group, the same protocol of endotoxin infusion was used and then followed at 30 min by the infusion via the central venous line of 30 mg/kg of II for 30 min.
We subsequently hypothesized that the vehicle of the II molecule
might be responsible for part of the effects observed. Therefore, we
studied two additional groups, each one including four animals that
received after isotonic saline or endotoxin an infusion of 80 ml vehicle
over a 30-min period.
In the groups receiving endotoxin, animals underwent a 7 ml/kg/h
infusion of isotonic saline beginning at the end of the endotoxin infusion and continued to maintain a mean arterial pressure (MAP) > 50 mm Hg. Vascular filling was stopped when MAP was > 50 mm Hg or
normalized after II administration.
Biologic Methods
Blood samples were collected from the arterial catheter in sterile
tubes at the same time as the data collection: at baseline and at 30, 60, 90, 120, 180, 240, and 300 min. No anticoagulant treatment was administered to the animals during the experiment. In the two groups receiving II, plasma levels of human II were measured by an enzyme-linked immunosorbent assay (ELISA) method using specific antibodies
raised again each heavy chain of II (11). We verified that pig plasma,
taken up before II administration, did not interfere with the assay at
the dilutions used.
Leukocyte and platelet counts were obtained on EDTA anticoagulated blood. For coagulation assays, blood (four parts ) was collected
in tubes containing 3.8% sodium citrate (one part). Prothrombin time
(PT) and fibrinogen levels (Clauss' method) were rapidly measured
by standard procedures. Other assays were performed on frozen
plasma stored at 
70° C. All tests were done with human procedures
and our own reference values were established as recommended (24)
(mean ± 2 SD, n = 50 baseline values). Heparin cofactor activity of
ATIII was determined by chromogenic assay (Coamatic® antithrombin; Biogenic, Maurin, France) (n = 70 to 125%). Thrombin-antithrombin complexes (TAT) were measured by an ELISA method
(Enzygnost® TAT; Behringwerke AG, Marburg, Germany) (n < 30 mg/L). Von Willebrand factor antigen (vWF) was measured by ELISA
(Asserachrom® vWF; Diagnostic Stago, Asnières, France) (n = 70 to
130%). Quantitative determination of free and complexed tissue-type
plasminogen activator (t-PA) was determined by enzyme immunoassay (TintElize® t-PA; Biopool, Stockholm, Sweden) (n < 2.5 mg/L). A
chromogenic assay (Coatest® PAI; Biogenic) (n = 20 to 55 AU/ml) was
used to determine free plasminogen activator inhibitor type 1 (PAI-1)
activity.
TNF plasma levels were detected with an ELISA method with
porcine anti-TNF antibodies (EP-TNF; Clinisciences, Montrouge, France).
Data Analysis
Results are given as mean ± SEM. Repeated-measures analysis of
variance and Fisher's PLSD test were used to determine significant differences. A value of p < 0.05 was considered significant. The plasma half-life (t1/2) of human II was derived from the mono-exponential curve that was fit to the plot of plasma concentration versus time, using regression analysis.
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Measurements of Human II Levels
We chose to investigate the post-treatment effects of human
II in a porcine model of endotoxin shock. We compared four
groups; control, II, LPS, and LPS + II. Initially, to establish
the appropriate II dosing regimen, we performed a pharmacokinetic study in piglets of the II group. They received 50 ml
of isotonic saline from 0 to 30 min of the protocol and then 30 mg/kg II over 30 min from 30 to 60 min. The plasma II
level, determined just after its injection, was 447 ± 23 mg/L. It
gradually and regularly declined during the course of the experiment, reaching 287 + 39 mg/L at 300 min. The II half-life
was 7.3 ± 1.9 h. We observed in the LPS + II group an earlier and more pronounced decrease in plasma II levels (Figure 1), which, however, remained still near 260 mg/L at 300 min.
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p < 0.05, IHemodynamic and Oxygenation Results
In the control and II groups, MAP, systemic vascular resistances (SVR), cardiac index mean pulmonary arterial pressure
(MPAP), pulmonary vascular resistances (PVR), oxygenation
parameters, and blood lactate remained stable throughout the
protocol. We did not observe any significant differences between these two groups. Likewise, leukocyte and platelet counts
and coagulation and fibrinolysis parameters were not modified after II infusion. Because no differences were found between the II group and the control group, only the changes in
hemodynamic and oxygenation parameters in the control,
LPS, and LPS + II groups are illustrated in the figures.
In the LPS and LPS + II groups, hemodynamic changes
were similar until 120 min and were significantly different
from the control group. After 120 min, the changes between
the LPS and LPS + II groups became different. In the LPS
group, the administration of endotoxin resulted in a significant
decrease in MAP (46%) and SVR (27%) at 120 min.
Throughout the protocol, 542 ± 82 ml of fluid was administered to maintain MAP > 50 mm Hg. However, despite this
resuscitation attempt, a significant fall in CI appeared at 240 and 300 min with an increase in blood lactate. Pulmonary capillary wedge pressure (PCWP) increased significantly at the end of the study (baseline = 7 ± 1.5 versus 300 min = 12 ± 2.5 mm Hg, p < 0.050. In the LPS + II group, the administration
of II normalized MAP at the end of the study with a significantly less pronounced decrease in cardiac index. Only 195 ± 38 ml of fluid was necessary to maintain MAP > 50 mm Hg in
the LPS + II group. SVR were not significantly modified by
the treatment (Figure 2).
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The endotoxin-induced alterations in oxygenation were evaluated by acidosis, hyperlactatemia, and OER. The latter two
increased in parallel. In marked contrast, after II administration, lactatemia (Figure 3), arterial pH (data not shown), and
the OER were clearly normalized.
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With regard to lung function, we observed a dramatic increase in MPAP (+65%) and PVR (+84%) 30 min after the
infusion of endotoxin. Similar responses were obtained in the
presence of II and they were paralleled with a strong decrease in the PaO2/FIO2 ratio. However, in the second part of
the observation period, a significantly less severe increase in
MPAP and PVR was observed after II administration, whereas
the evolution of the PaO2/FIO2 ratio was similar with or without
II (Figure 4).
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In order to verify that the vehicle of II could not be responsible for part of the observed effects, we studied two additional groups that received, after isotonic saline or endotoxin,
an infusion of 80 ml vehicle over a 30-min period. In these two
groups, the evolution of hemodynamic and oxygenation parameters were not different from the control or LPS groups,
respectively (data not shown).
Hematologic Results
In the control and II groups, all parameters remained stable
during the protocol. In both groups receiving endotoxin, white blood cell counts rapidly decreased (69% at 30 min) and remained very low throughout the entire study. Circulating
platelets also progressively diminished during the experiment
(62% at 300 min) without improvement after II administration (Figure 5).
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In both LPS groups, a dramatic procoagulant response was
demonstrated, partially corrected by II administration (Figures 5 and 6). A severe decrease in PT (53%) and fibrinogen
(58%) was observed in the LPS group. TAT levels began to
increase at 90 min, achieving a maximum level (53 times the
baseline value) at 300 min, associated with a significant decrease in ATIII activity. In the LPS + II group, the decrease
in PT and fibrinogen was not as severe (29% and 36%, respectively); there was also a significant decrease in TAT levels
at the end of the experiment compared with the LPS group
(63% at 300 min). The LPS-induced activation of the fibrinolytic system was manifested by a rapid increase in t-PA levels,
peaking at 120 min, which was not modified by II administration. Following the early activation of fibrinolysis, the increase
in PAI-1 levels was significantly less pronounced in the LPS + II group (38% at 300 min compared with LPS group) (Figure 6). vWF plasma levels, assessed to evaluate endothelial damage, increased in both LPS groups without modification of
II administration.
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Because II could interfere in TNF production, we measured TNF levels in the four groups. They were stable and in
a normal range in the control and II groups. After endotoxin
administration, very high levels of TNF were evidenced,
peaking at 90 min (in the LPS group: baseline = 15 ± 5 pg/ml
versus 90 min = 36,033 ± 6,310 pg/ml, p < 0.05), whereafter
they decreased at 180 min until the end of the experiment
without normalization by 300 min (Figure 7). These results
were not significantly modified by II administration.
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The main goal of this study was to evaluate whether II administration could improve hemodynamic and coagulation parameters in experimental septic shock. Pigs were chosen as a clinically relevant species, resembling to humans in various functions
as assessed by cardiovascular, respiratory, and biochemical parameters (23, 25). In the present porcine model the administration of endotoxin was followed by hypotension, vasodilation,
and decreased cardiac output. We used a low rate of vascular
filling after endotoxin administration to avoid hemodilution and
modification of coagulation parameters and we decided to modulate the vascular filling to maintain MAP > 50 mm Hg rather
than keeping volume constant and allowing pressures to vary.
This vascular filling regimen maintained a cardiac index close
to control animals and a PCWP stable until the third hour of
the experiment. A late significant increase in PCWP was seen
in the LPS group, concurrent with a decrease in cardiac index.
These hemodynamic changes were close to the results observed in other animal models (23, 26).
During septic shock in humans, a large consumption of II
has been reported (27), suggesting that a substitutive therapy by this protein could be of interest to restore the proteinase-antiproteinase balance. We thus chose to investigate the effects
of II given after endotoxin administration. Because II metabolism remains largely unknown, we verified for the first time
that a single infusion of 30 mg/kg human II over 30 min was
sufficient to achieve throughout the observation period circulating II plasma levels higher than the normal human plasma
concentrations (250 mg/L). In our study, the plasma II level
peaked at 447 mg/L just after the end of the infusion and remained greater than normal human plasma concentrations until 300 min. In the II group, the half-life of II was estimated
to 7.3 h on the basis of a monocompartmental model. In contrast, after endotoxin infusion, the II plasma concentration decreased more rapidly. These data were consistent with an
increased consumption of the molecule.
The hemodynamic results of our study are consistent with a
favorable effect of II infusion. The decrease in cardiac index was not as severe in animals receiving II, and in addition
MAP was completely normalized at the end of the study. In
the treated group, the oxygen extraction ratio remained stable
and in the normal range throughout the experiment. Sequential measurements of blood lactate showed that the increase in
lactate levels was completely blunted by II administration.
This improvement was not due to vascular filling since animals
treated with II received less fluid than animals in the LPS
group. Tani and associates (28) studied the effects of Ulinastatin (bikunin) in an acute model of septic shock in dogs inoculated with bacteria. In this model also, Ulinastatin administration was associated with an improvement in the hemodynamic
parameters with a normalization of the cardiac index and MAP.
In our model, the hemodynamic effects of II seemed to be
related to an increase in cardiac function rather than in vascular tone. SVR were not significantly modified by II administration. It remains to be documented whether this improvement is linked to an increase in cardiac contractility or a change
in diastolic compliance. To confirm that the hemodynamic improvement was due to II treatment and not to its vehicle, we studied two other groups of animals, one receiving the vehicle of the molecule, the second receiving endotoxin and then the
vehicle. Compared with the control and LPS groups, respectively, no significant difference in hemodynamic and oxygenation parameters could be observed.
Endotoxin administration usually results in the development
of an acute pulmonary hypertension with an increase in PVR
and hypoxemia. In previous studies in the same animal model,
histologic findings supported the development of a respiratory
distress syndrome with marked pulmonary leukocyte sequestration and interstitial edema (29). In our study, II administration was associated with a significant decrease in endotoxin-induced pulmonary hypertension. The lack of significant
difference in the PaO2/FIO2 ratio between both septic groups
might be explained by an underestimation of the actual pulmonary shunt, induced by the decreased cardiac index in the
LPS group. Overall, these results suggest that II might protect the lung during endotoxemia.
Few studies have been designed to determine the effects of
proteinase inhibitors on endotoxin-induced DIC. It is now admitted that the activation of the coagulant system plays a pivotal role in the pathogenesis of sepsis and in the development
of multiple-organ failure (5, 30). Recent studies on the effects
of low doses of endotoxin or TNF in human volunteers (4,
31) and in animal models of septic shock (32) have indicated
that these agents may create in vivo an imbalance between coagulation and fibrinolysis, resulting in a procoagulant state. In
our study, a similar imbalance was observed and administration of endotoxin resulted in the activation of coagulation and
fibrinolysis. The increase in TAT levels and the decrease in
platelets and PT and fibrinogen levels were all consistent with
the activation of coagulation. The early increase in t-PA was
consistent with an activation of fibrinolysis, counteracted by the
late increase in PAI-1 levels. In our model, human II administration significantly modified the evolution of coagulation and
fibrinolysis. II administration was associated with a lower activation of coagulation, mainly reflected by lower TAT levels at the end of the protocol. However, there was only a trend to a lesser decrease in platelets and fibrinogen levels. It may be hypothesized that the observation time after II administration was too short to measure statistically significant changes
in coagulation parameters. On the other hand, our results are
consistent with an improvement in fibrinolysis after II infusion. We observed a significantly lesser increase in PAI-1 at 4 and 5 h of the study. No significant differences in vWF plasma
levels could be observed, suggesting that II did not modify
the severity of endothelial injury. These results are consistent
with a favorable effect of II on endotoxin-induced DIC,
maybe by modulation of monocyte activation. However, II is
known to inhibit plasmin activity (13) and this inhibitory effect may be enhanced in case of inflammatory disorders (33).
Indeed, further studies are required to determine the true influence of II on the fibrinolytic system in vivo.
The results reported in this work provide evidence that II
exerts a protective effect in the endotoxic shock model. The
mechanism of this effect was not elucidated by the current study.
II and bikunin appear to induce similar effects on hemodynamic parameters and tissue oxygenation markers. Therefore,
we suggest that II allows a local release of bikunin in inflammatory foci. The hyaluronic acid-binding capacity of II would
be required for this targeted delivery, as recently discussed (34).
The potential therapeutic activity of bikunin was formerly explained by its antiproteinase activity. However, compared with
other plasma proteinase inhibitors, its inhibitory capacity is
weak (13). Indeed, the ATIII consumption which may be
partly due to a proteolytic cleavage by HLE was not reduced
by II administration. Furthermore, the biologic effects of other
proteinase inhibitors such as hirudin (9) and eglin (10) appeared to be very different (e.g., systemic hypotension unchanged) from those induced by II treatment. Thus, it may
be hypothesized that bikunin and therefore II exert an anti-inflammatory effect by other mechanisms. Bikunin has been
reported to inhibit the production and activity of some cytokines: TNF, IL-1, IL-6, and IL-8 (16). For that reason, we
determined plasma TNF levels in the piglets challenged with
endotoxin and we did not find any significant difference with
or without II administration. More extended trials should be
performed to elucidate the mechanisms by which II develops
its effects and, overall, to confirm in other animal models its
potential therapeutic activity.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Prof. F. Fourrier, Service de Réanimation Polyvalente, Hôpital Roger Salengro, Boulevard du
Professeur Leclercq
CHRU, 59037 cedex Lille, France.
(Received in original form November 15, 1996 and in revised form August 7, 1997).
Presented in part at the Annual Meeting of the American Thoracic Society, New Orleans, May 1996.
Acknowledgments:
The writers are indebted to Dr. Brad Brazeal (University
of Texas Medical Branch, Galveston, TX) and Julie Pattou (Laboratoire de
culture cellulaire, Faculté de Medecine, Lille, France) for their useful assistance in the completion of the manuscript, Dr. Patrick Gosset (INSERM U416,
Institut Pasteur, Lille, France) for measurements of TNF levels, and Anne
Dickès for skillful laboratory assistance.
Supported by grants from Université de Lille II ER No. 150 (F. Fourrier) and EA No. 1052 (J. Mizon) and Laboratoire Français du Fractionnement et des Biotechnologies (LFB): Les Ulis, F. Conseil Régional du Nord-Pas de Calais.
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References |
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DISCUSSION
REFERENCES
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