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ABSTRACT |
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Gram-negative septic shock is mediated in part by endotoxin (lipopolysaccharide; LPS), and animal
models have shown that blockade of even single adhesion molecules considerably improves survival. Thus interference with the adhesion cascade may provide a useful therapeutic approach in human
sepsis. Young healthy men (n = 30) each received a bolus of 4 ng/kg LPS intravenously to study the effects of endotoxemia on adhesion processes in humans and to identify potential targets for pharmacologic intervention. One third of subjects received pretreatment with 1,000 mg aspirin and 1,000 mg paracetamol to study potential antiinflammatory effects of aspirin or effects of antipyresis. Circulating neutrophils dropped by 
80% at 67 min after LPS, monocytes by 96% at 90 min, and lymphocytes by 85% at 240 min. L-selectin expression decreased, particularly on monocytes. Circulating (c)E-selectin levels increased by 820%, von Willebrand factor-Ag (vWF), soluble thrombomodulin, circulating (c)P-selectin, circulating intercellular adhesion molecule-1 (cICAM-1), and circulating vascular cell adhesion molecule-1 (cVCAM-1) by a mean of 65 to 98% (p < 0.001 for all), but cL-selectin by only 15%. Urinary excretion of soluble adhesion molecules was negligible. Aspirin had no influence on the LPS-induced changes of adhesion parameters, but paracetamol blunted the relative increase in vWF while having no effects on the other parameters measured. The consistent, profound,
and early upregulation of cE-selectin during endotoxemia indicates that cE-selectin may be a better surrogate marker to monitor the activation status of endothelial cells in systemic inflammation than
the other markers measured. Although aspirin did not have any antiinflammatory effects in this
model, paracetamol lowered the relative increase in vWF.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHOD
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The recruitment of circulating blood cells to sites of endothelial activation plays a crucial role in a number of pathophysiologic events, including inflammation, blood coagulation, and the immune response (1). Animal studies indicate that these platelet-leukocyte- endothelial interactions are also of utmost importance in the development, propagation, and outcome of sepsis (2). Among other bacterial mediators (3) lipopolysaccharide (LPS, endotoxin) contributes to gram-negative sepsis.
LPS strongly stimulates the expression of adhesion molecules on endothelial cells (EC): EC upregulate E-selectin in response to LPS, which is followed by the release of soluble E-selectin into the bloodstrean in vivo (4, 5). As a consequence plasma levels of circulating (c)E-selectin are augmented in sepsis (6, 7). The increase in cE-selectin appears to depend on the dose of LPS (4), and is determined by the LPS-enhanced tumor necrosis factor (TNF) production (5, 8).
Interestingly, cE-selectin levels correlate with cardiovascular compromise and clinical outcome in septic patients (7, 9). Similarly, levels of cP-selectin (10), circulating intercellular adhesion molecule-1 (cICAM-1) (9, 11), and vascular cell adhesion molecule-1 (cVCAM-1) are increased in sepsis and may predict organ dysfunction in septic patients (6, 12, 13). Conversely, plasma levels of L-selectin, which is continuously shed from leukocytes into the bloodstream, are lowest in critically ill patients who progressed to adult respiratory distress syndrome (14). Unfortunately the differences in study designs between these trials do not allow direct comparison of the prognostic value of these markers of endothelial, platelet, and leukocyte activation. Nor do these studies allow conclusions on the time course and mechanisms of regulation of cAM.
In the current study we aimed to further characterize the
time sequence of the regulation of these cell activation markers: we therefore infused endotoxin into healthy volunteers;
this procedure presents an established model of human inflammation (15). We measured plasma levels of the endothelial cell markers, cE-selectin, von Willebrand factor (vWF) antigen, and of thrombomodulin, the leukocyte activation marker
cL-selectin, cP-selectin, a marker of platelet and/or endothelial
activation, cICAM-1, and cVCAM-1. In addition we determined differential blood counts and quantified L-selectin expression on leukocytes and P-selectin expression on platelets.
Secondly, we hypothesized that aspirin could inhibit adhesive
events because it has inhibitory effects on the LPS-induced nuclear translocation of NF-
B in vitro, which transcriptionally regulates several "immediate early genes" such as TNF
(16). Hence, the effects of aspirin-pretreatment were compared with placebo and with paracetamol. Paracetamol was
used as an active substance to control for potential effects of
inhibiting the febrile response because hyperthermia may enhance L-selectin-dependent adhesion (17) and may increase
plasma levels of cICAM-1 (18).
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METHOD |
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ABSTRACT
INTRODUCTION
METHOD
RESULTS
DISCUSSION
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Study Design and Study Subjects
The study was randomized, double-blind, placebo controlled in three parallel groups (n = 10/group) in 30 healthy male subjects (mainly students). The study was approved by the Ethics Committee of the Vienna Medical School, and all participants gave written informed consent prior to enrollment in the study. Mean age of the study subjects was 28 ± 5 yr (± SD) and mean body mass index was 24 ± 2.3 kg/m2. Health status was determined by a battery of laboratory and clinical tests, including evaluation of medical history, physical examination, and hematologic, biochemical, virologic, and drug screening as previously described (19). Exclusion criteria were hypersensitivity to either aspirin or paracetamol and regular or recent (within 3 wk) intake of any drugs, including over the counter medication.
Study Protocol
Volunteers reported at the study ward at 8:00 A.M. after an overnight fast. Throughout the entire study period they had to stay in bed in supine position and were kept fasting for 8.5 h after endotoxin infusion. A 5% glucose infusion (Leopold Pharma) was started at 8:30 A.M. and continued for 8.5 h at 3ml/kg/h to ascertain constant blood glucose levels and adequate urinary output. Placebo (generously provided by Genericon Pharma, Lannach, Austria), 1,000 mg paracetamol (Paracetamol; Genericon), or 1,000 mg acetylsalicylic acid (ASS; Genericon) were administered orally after start of the glucose infusion. At 9:00 A.M. study subjects received 4 ng/kg LPS (National Reference Endotoxin, Escherichia coli; United States Pharmacopoeial Convention Inc., Rockville, MD) as an intravenous bolus infusion for 1 to 2 min.
Vital parameters were monitored continuously (ECG, heart rate, and oxygen saturation) or at 20-min intervals (blood pressure) on a Care View System (Hewlett Packard, Böblingen, Germany). Tympanic temperature was recorded hourly using an electronic thermometer (Thermoscan, San Diego, CA) and 24 urine samples were collected before and on the study day. For safety reasons, study subjects had to stay at the research ward overnight until 24 h after endotoxin infusion.
Sampling and Analysis
Venous blood was drawn into vacutainer tubes before administration
of any drug and thereafter, as indicated in the figures, until 8 h after
endotoxin injection by repeated venipunctures (except differential
blood counts, which were obtained from an indwelling venous line) on
the arm opposite where LPS had been administered. All blood samples were predetermined and based on the results from previous studies (15, 20): plasma was obtained before LPS, at 1, 1.5, 2, 3, 4, 8, and 24 h, and additional samples for differential blood counts were
drawn at 7-min intervals from 45 to 90 min, at 105 and 150 min (Figure
1). Citrated plasma was obtained by centrifugation at 2,000 × g for 15 min at 4° C and stored at 80° C until analysis as duplicates, and all
samples from individual subjects were run in the same assay.
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Soluble adhesion molecules were determined from citrated plasma
and urine by enzyme immunoassays (R&D Systems, Oxon, UK) as described previously (19). Intra-assay, day-to-day and within-day variability have been described previously (19): a small but significant
diurnal decrease of cE-selectin and cP-selectin levels (
8%) was observed, and the coefficient of variation for the intra-assay, day-to-day,
and within-day variability averaged less than 6, 8, and 5%, respectively. Ofloxacin (400 mg) was added to urine containers to avoid bacterial degradation of excreted adhesion molecules. Plasma levels of
soluble thrombomodulin (sTM) were assayed by EIA from Diagnostica Stago (Chausson, Asnieres-sur-Seine, France), and vWF by EIA
using polyclonal antisera (Dako-Patts, High Wycombe, UK) as described earlier (24).
Blood counts. Differential blood counts were performed with a cell counter (Sysmex, Japan). However, microscopic inspection of blood smears revealed spuriously high monocyte counts at times when neutrophilia was present. Hence, monocyte counts were calculated from scatter histograms obtained with the flowcytometer.
Flowcytometric assay. Because all samples required immediate
processing to avoid artificial activation of leukocytes or platelets, leukocytes were stained only at 30 and 90 min, and at 6 and 24 h. All
antibodies except CD14 (Phycoerythrin labeled; DAKO) were fluoro-isothiocyanate labeled and purchased from Immunotech International (Marseille, France) (CD62P, CD62L, isotypic IgG control). Flowcytometric analysis was performed as described previously (23, 25, 26). Twenty thousand and thirty thousand events were gated for leukocytes and platelets, respectively. We did not perform analyses of
monocytes at 90 min or 6 h after intravenously administered LPS because of the low number of circulating monocytes at 90 min and the
highly variable monocyte counts at 6 h. The parameters of the flow cytometer did not change significantly during the study, as verified by means of calibration beads (Quantum Fluorescence kits; Flow Cytometric Standard Corp., San Juan, PR) on a daily basis.
Data Analysis
As hemodilution was only minimal (< 5% at 5 h), data were not adjusted for hemoglobin levels. Data are expressed as the mean and the
95% confidence intervals and presented as maximal percental changes
for description in the text (n = 30). Absolute values are presented in
the figures. Nonparametric statistics were applied. All statistical comparisons within groups were done with Friedman's ANOVA and the
Wilcoxon's signed ranks test for post hoc comparisons. To test
changes in end points between groups for statistical significance the
Kruskal-Wallis ANOVA was used and post hoc comparisons were performed by the Mann-Whitney U test. A two-tailed p value of 0.05 was considered significant.
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RESULTS |
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METHOD
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DISCUSSION
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The usual side effects of endotoxin were observed (e.g., chills, fever, headache, nausea, myalgia). Expectedly (27), paracetamol decreased the febrile response (maximum temperature, 38.5° C (CI: 38.1 to 38.8) and 37.6° C (CI: 37.2 to 37.9) in the placebo and paracetamol groups, respectively). Aspirin delayed the onset of fever by 1 h but it did not decrease the maximal increase in temperature seen at 4 h after LPS administration. No unexpected adverse events occurred.
Changes in Differential White Blood Cell Counts
Neutrophil counts dropped by a maximum of 80% (95% CI for the nadir: 77 to 83%) at 67 min after LPS infusion, which was followed by a rapid recovery within 40 min (Figure 1). In the placebo and the aspirin groups a second dip of leukocyte counts was observed at 150 min, which was rather blunted in the paracetamol group. Thereafter, neutrophil counts increased steadily to reach a plateau at 8 h (Figure 1).
Lymphocyte counts decreased continuously by a maximum of 83% (CI: 81 to 85%) and the nadir occurred at 280 min (CI: 260 to 303 min), although the most rapid fall was observed together with the maximal neutropenia (Figure 1; p > 0.05 between groups).
Monocyte counts averaged 0.52 G/L (0.45 to 0.52) at baseline and decreased to 0.01 G/L (CI: 0.007 to 0.012) at 90 min. At 6 h monocyte counts ranged from 0.16 to 0.93 G/L, indicating marked variability in the duration of monocytopenia, and at 24 h they were slightly above baseline (p > 0.05 between groups).
L-Selectin Expression and Shedding of L-Selectin
L-selectin+ neutrophils decreased from a baseline of 96% (CI: 94 to 97%) to 90% (CI: 87 to 93%) at 6 h. L-selectin+ monocytes decreased from a baseline of 90% (CI: 88 to 92%) to 82% (CI: 79 to 85%) at 24 h. The MFI of neutrophils increased slightly from baseline values of 119 (CI: 108 to 130 arbitrary units) to 138 (CI: 122 to 154) at 90 min and fell to nadir levels of 92 (CI: 82 to 102) at 6 h. This effect was considerably more pronounced on monocytes: 107 (CI: 94 to 119) before intravenously adminstered LPS and 55 (CI: 48 to 62) at 24 h (Figure 2; p > 0.05 between groups).
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A consistent but small increase in cL-selectin was observed (11%; CI: 7 to 14%), and cL-selectin levels stayed at 7 to 10% above baseline levels throughout the observation period (Figure 3; p > 0.05 between groups).
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Specific Markers of Endothelial Activation
Soluble thrombomodulin increased by 86% (CI: 58 to 113%) at 3 h, and vWF-Ag increased by 98% (CI: 77 to 119%) at 4 h (Figure 4). Baseline vWF levels were somewhat higher in the paracetamol group (p > 0.05). The percental increase in the paracetamol group was significantly lower than in both other groups from 2 to 4 h after LPS administration (p < 0.05). The increase in cE-selectin by 795% (CI: 697 to 894% at 8 h) was considerably more pronounced than that of all other markers (Figure 3; p > 0.05 between groups).
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P-Selectin on Platelets and Platelet/ Endothelial-derived cP-Selectin
As expected from a previous study (28) platelet counts decreased from baseline values of 234 × 109/L (CI: 216 to 251)
by 14% (CI: 17 to 12%) at 75 min after LPS infusion and
stayed at those levels until 6 h after intravenously administered LPS. P-selectin+ platelets did not increase above baseline levels 0.6% (CI: 0.3 to 0.9%) at 2, 4, 6, or 24 h (p > 0.05)
and even decreased slightly at 2 h (0.4% CI: 0.2 to 0.6%; data
not shown). cP-selectin levels increased by 97% (73 to 122%)
and mean cP-selectin levels of the aspirin-treated subjects always remained slightly above the other two groups. (Figure 3;
p > 0.05 between groups).
Soluble Adhesion Molecules of the Immunoglobulin Superfamily
cICAM-1 increased by 99% (CI: 86 to 112%) at 8 h and cVCAM-1 by 73% (CI: 66 to 80%) at 24 h (Figure 5; p > 0.05 between groups).
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Urinary Excretion of Circulating Adhesion Molecules
As indicated by the data in Table 1, soluble P-selectin was not detectable in urine, and urine levels of the other soluble adhesion molecules were also very low: when considering the estimated plasma volume in our subjects (about 3,000 ml), less than 6% of cVCAM-1 was recovered in 24-h urine samples and substantially less for the other cAM.
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Salicylate Levels and TNF Levels
Salicylate levels averaged 0.21 mM/L (CI: 0.13 to 0.28) at 60 min and stayed at that level until 180 min (0.22 mM/L; CI: 0.16 to 0.27) after ingestion of aspirin.
Plasma levels of TNF increased by 3 log cycles in all groups (p < 0.001): peak plasma levels were reached between 90 and 120 min and averaged 4.1 ng/ml (range: 0.6 to 13.3) in the placebo group, 3.0 ng/ml (range: 0.6 to 6.8) in the paracetamol group, and 4.7 ng/ml (range: 0.6 to 24.6) in the aspirin group (p > 0.05 between groups).
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Although animal models provide evidence that adhesion molecules contribute to the pathogenesis of sepsis (2, 29), data on the LPS-induced regulation of adhesion events in humans are scarce. Hence, we have used LPS-infusions as a model to elicit a systemic inflammatory reaction in humans (15).
In contrast to previous LPS trials, the more frequent sampling in our study provided a better estimate of an 80% drop in neutrophils (Figure 1). As LPS-infusion precipitates an early P-selectin-dependent neutropenia in rats (30), it would be tempting to study the pharmacodynamics of P-selectin antagonists in this LPS-model. Whereas the neutropenia was rapidly reversible, the concomitant lymphocytopenia was more sustained (Figure 1). As L-selectin mediates lymphocyte homing, an LPS-induced upregulation of ligands for L-selectin could be responsible for this effect. In addition, L-selectin is not only a bystander mediating rolling of leukocytes but may be a signaling receptor for LPS also (31). Hence, its regulation is of interest: only a small decrease in L-selectin+ leukocytes occurred similar to a previous study (4). However, there was a substantial decrease in the MFI, particularly of monocytes (Figure 2). As the MFI of L-selectin on neutrophils inversely correlated with neutrophilia during inflammation (32), it has been suggested that downregulation of L-selectin by shedding might in part explain the appearance of neutrophilia during inflammation. However, there was only a 10% increase in cL-selectin in plasma (Figure 3). The marginal increase in cL-selectin as compared with the other markers may be due to the high background noise caused by continuous shedding of cL-selectin. Hence, cL-selectin, in contrast to neutrophil elastase (28), is a poor marker to detect LPS-induced neutrophil activation in vivo.
In contrast to cL-selectin, there was an outstanding eightfold increase in cE-selectin (Figure 3). This agrees with an animal study demonstrating that E-selectin expression is particularly sensitive to LPS-stimulation (33). A clinical report recently showed that cE-selectin levels measured on Day 1 after admission to the intensive care unit predicted outcome in critically ill patients (7). As in previous studies (4, 5, 8), there was no overlap in plasma E-selectin levels of baseline samples and those obtained at 4 to 8 h (Figure 3). Hence, compared with the other markers of endothelial cell activation measured (vide infra), cE-selectin levels could be particularly useful to monitor endothelial cell activation during the early course of severe sepsis (9).
Plasma levels of vWF, another specific endothelial marker, doubled within 4 h (Figure 5), which is in general agreement with previous studies (28, 34). The relative increase in vWF was lowest in the paracetamol group (Figure 5). Interestingly, the increase in vWF is at least in part mediated by TNF (28). However, paracetamol did not significantly suppress TNF levels. Further, it seems unlikely that paracetamol had an effect on endotoxin signaling because vWF was the only molecule affected by pretreatment with paracetamol. It is of note that basal vWF levels were somewhat higher in the paracetamol group. This could be due to continuous vWF release from its intraendothelial storage site, and those subjects may therefore secrete less vWF in response to an inflammatory stimulus such as LPS. Alternatively, muscular exercise is known to increase vWF antigen levels (35), and the muscular work needed to increase body temperature to maximal levels may have been greater in the placebo group than in the paracetamol group. Hence, the relatively lower increase in vWF may also be attributable to less muscle rigor. Finally, vWF is a well-known acute-phase reactant (36). Although paracetamol is known to have only weak antiinflammatory potential, it is conceivable that a yet unidentified antiinflammatory action of paracetamol selectively dampened the increase in vWF.
Like vWF, plasma levels of sTM increased rapidly and reached maximal levels at 3 h. Thrombomodulin is downregulated rather than upregulated on endothelial cells by cytokines in vitro (33). Thus, sTM seems to be shed into plasma either by endothelial sloughing or proteolytic cleavage from the endothelial cell surface. It is interesting that the kinetics of sTM were faster (Figure 5) than for the other markers measured, further supporting the different regulation, i.e. downregulation rather than upregulation. Unfortunately, determination of plasma levels does not allow for direct quantification of surface-expressed activation markers because of the time lag between maximal expression and shedding. Yet the observation that cICAM-1 and cVCAM-1 levels reached a plateau at 24 h (Figure 4) is in good agreement with the later upregulation of these molecules as compared with E-selectin.
Another issue that merits discussion is the increase in cP-selectin (Figure 3), which was not accompanied by an increase in circulating P-selectin+ platelets. Hence, it is questionable if determination of P-selectin expression on platelets is of diagnostic value in patients with septicemia. This can possibly be explained by margination of activated platelets and concomitant shedding of P-selectin from the platelet surface into the bloodstream (37, 38).
Finally, our data show that neither paracetamol nor aspirin
had an acute effect on the LPS-induced adhesion events. This
is in contrast to the cyclooxygenase inhibitor ibuprofen (39), which enhances LPS-induced TNF levels. It may be worthwhile to investigate the reason for this difference between aspirin and ibuprofen in subsequent trials. Recently, it was
shown that aspirin concentration-dependently inhibits the
LPS-induced nuclear translocation of NF-B in vitro (16, 40).
NF-B transcriptionally regulates several "immediate early
genes" such as TNF or E-selectin. This does not appear to
translate into a measurable effect on any downstream events
in vivo because E-selectin shedding and neutrophilia, which are critically dependent on TNF (5), were unaffected by administration of 1,000 mg aspirin. This could be explained by
the average plasma salicylate levels of 0.2 mM/L in our study,
which indicate that the IC50 of salicylate (1.5 mM in vitro) (16)
was not reached in vivo. Yet, aspirin was administered at the
maximum single dose approved. The usual dose for antipyresis is 300 to 600 mg and for analgesia 300 to 900 mg, every 4 to
6 h, with a maximum daily dose of 4 g. However, it is conceivable that repeated aspirin intake, which leads to an accumulation of aspirin, may yield different results. This must be regarded as a limitation of our study.
Finally, we have to address an important issue: while endotoxemia may provide insights into gram-negative septic shock, there may be significant differences between clinical septic shock and experimental endotoxemia. In particular LPS is a noninfectious mediator, with self-limited consequences in our setting. Hence, it may be very difficult to extrapolate results from studies such as the present one to the clinical situation.
In conclusion, the profound LPS-induced leukopenia could provide a suitable surrogate end point for testing the efficacy of antiadhesive drugs. The consistent, profound, and early upregulation of cE-selectin during endotoxemia indicates that cE-selectin may be a better suitable surrogate end point to monitor the activation status of endothelial cells in systemic inflammation than the other markers measured. Although aspirin did not have any antiinflammatory effects in this model, paracetamol lowered the relative increase in vWF.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Bernd Jilma, M.D., Department of Clinical Pharmacology-TARGET, The Adhesion Research Group Elaborating Therapeutics, Vienna University Hospital School of Medicine, Währinger Gürtel 18-20, A-1090 Wien, Austria.
(Received in original form May 27, 1998 and in revised form October 14, 1998).
Acknowledgments: The writers are indebted to Inge Wallner, RN, and Alexandra Rauch, RN, for their excellent assistance.
Supported by a grant from the Kamillo-Eisner Stiftung, CH.
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References |
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