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CRITICAL CARE AND TRAUMA

Epinephrine Enhances Platelet-Neutrophil Adhesion in Whole Blood In Vitro

Nicola A. Horn, MD^*, Denisa M. Anastase, MD, Klaus E. Hecker, MD^*, Jan H. Baumert, MD^*, Tilo Robitzsch, MD, and Rolf Rossaint, MD, PhD^*

*Department of Anesthesiology, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany; Department of Anesthesiology, Spitalul Clinic de Ortopedie Foisor, Bucuresti, Romania; and Institute of Transfusion Medicine, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany

Address correspondence and reprint requests to Nicola A. Horn, MD, Department of Anesthesiology, Rheinisch-Westfälische Technische Hochschule Aachen, Pauwelsstraße 30, 52074 Aachen, Germany. Address e-mail to nhorn{at}ukaachen.de.

	Abstract

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Previous studies showed that - or ß-adrenoceptor stimulation by catecholamines influenced neutrophil function, cytokine liberation, and platelet aggregability. We investigated whether adrenergic stimulation with epinephrine also alters platelet-neutrophil adhesion. This might be of specific interest in the critically ill, because the increased association of platelets and neutrophils has been shown to be of key importance in inflammation and thrombosis. For this purpose, whole blood was incubated with increasing concentrations of epinephrine (10 nM, 100 nM, and 1 µM). To distinguish receptor-specific effects, a subset of samples was incubated with propranolol (10 µM) or phentolamine (10 µM) before exposure to epinephrine. After incubation, another subset of samples was also stimulated with 100 nM of N-formyl-methionyl-leucyl-phenylalanine. All samples were stained, and platelet-neutrophil adhesion and CD45, L-selectin, CD11b, P-selectin glycoprotein ligand-1, glycoprotein IIb/IIIa, and P-selectin expression were measured by two-color flow cytometry. Epinephrine significantly enhanced platelet-neutrophil adhesion and P-selectin and glycoprotein IIb/IIIa expression on platelets. CD11b and L-selectin expression on unstimulated neutrophils remained unchanged, whereas N-formyl-methionyl-leucyl-phenylalanine-induced upregulation of CD11b and downregulation of L-selectin were suppressed by epinephrine. ß-Adrenergic blockade before incubation with epinephrine increased platelet-neutrophil aggregates and adhesion molecule expression (CD11b, P-selectin, and glycoprotein IIb/IIIa) even further. These results demonstrate that epinephrine enhances platelet-neutrophil adhesion. The -adrenergic receptor-mediated increase in P-selectin and glycoprotein IIb/IIIa expression on platelets may contribute substantially to this effect. Our study shows that inotropic support enhances the platelet-neutrophil interaction, which might be crucial for critically ill patients.

	Introduction

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An increased association of activated platelets with leukocytes contributes to the pathophysiology of unstable angina, myocardial infarction, cardiopulmonary bypass, thrombosis, and sepsis (1–3). There is evidence that cells involved in such heterotypic conjugates perform intercellular communication and facilitate thrombin generation and leukocyte rolling and migration, thus contributing to the course of the pathologic process (4–7). Catecholamine concentrations are increased as an early stress response after cardiac arrest, myocardial infarction, and trauma. Therapeutically, they are used in critically ill patients to treat low cardiac output and severe hypotension. Previous studies have shown that epinephrine modulates the unspecific immune response. It decreases neutrophil adherence, chemotaxis, and phagocytic capacity (8–10). Epinephrine also inhibits tumor necrosis factor (TNF)- and interleukin (IL)-1ß production but enhances IL-8 and IL-10 production and L-selectin expression in monocytes (11–14). Epinephrine also enhances P-selectin expression in platelets and the opening of glycoprotein (GP)IIb/IIIa binding sites for fibrinogen, and it favors platelet aggregation (15–17).

Little is known about the effects of epinephrine on platelet-neutrophil adhesion at concentrations observed during therapeutic inotropic support or major injury. Knowledge of such effects may have implications not only for understanding endogenous stress hormone influences during injury, but also for the therapeutic use of catecholamines in patients with septic shock or cardiac failure. Considering the above-described changes in leukocyte and platelet function, we hypothesized that epinephrine could enhance platelet-neutrophil conjugate formation because of changes in adhesion molecule expression. Hence, we first studied the effects of epinephrine on platelet-neutrophil adhesion and adhesion molecule expression by using an established whole-blood model and two-color flow cytometry. Because epinephrine exhibits both and ß effects and platelets and neutrophils possess adrenoceptors, in a second step we used - and ß-adrenergic receptor-blocking drugs to identify the adrenergic receptors possibly involved in epinephrine-induced immunomodulation.

	Methods

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The following were purchased from BD Pharmingen (San Jose, CA): anti-CD41a-phycoerythrin (PE; clone HIP8) monoclonal antibody (mAb) recognizing platelet GPIIb/IIIa complex; anti-CD62P-fluorescein isothiocyanate (FITC; clone AK-4) mAb directed against P-selectin expressed on platelet surface; anti-CD45-FITC (clone HI30) mAb for leukocyte common antigen; anti-CD62L-PE (clone Dreg 56) L-selectin-binding mAb; anti-CD11b-PE (clone ICRF44) CD11b-binding mAb; anti-CD162 (clone KPL-1) mAb recognizing P-selectin GP ligand-1 (PSGL-1); anti-negative immunoglobulin G1-FITC and immunoglobulin G1-PE antibodies (clone MOPC-21); antibodies for nonspecific binding; and FACSlysing solution. Dulbecco’s phosphate-buffered saline (PBS) without Ca²⁺ and Mg²⁺, bovine serum albumin (BSA), epinephrine, paraformaldehyde, and N-formyl-methionyl-leucyl-phenylalanine (FMLP) were obtained from Sigma Chemicals (St. Louis, MO). FMLP is a physiological agonist of the FMLP receptor on the neutrophil cell surface. Activation of the FMLP receptor results in downregulation of PSGL-1 and L-selectin, whereas CD11b expression is increased.

After we obtained informed written consent from subjects and approval from the local ethics committee, blood samples were taken from 10 healthy volunteers who had not received any medication for at least 2 wk. Venous blood was carefully collected without a tourniquet from a cubital vein by using a 20-gauge butterfly needle. The first 3 mL of blood was used to perform a hemogram and was then discarded; the next samples were drawn into polypropylene tubes containing sodium citrate. Nine parts of blood were anticoagulated with one part of 3.8% trisodium citrate. All blood samples were immediately diluted 1:1 with 37°C prewarmed PBS, placed in sterile polypropylene tissue culture dishes (Sarstedt, Nuermbrecht, Germany), and incubated with 10 nM/L, 100 nM/L, or 1 µM/L (final concentrations) epinephrine. These concentrations approximately represent, respectively, a small therapeutic and a large therapeutic dose and a rather supramaximal concentration, although such a concentration might be achieved in case of cardiopulmonary resuscitation. For the experiments with antiadrenergic drugs, the samples were incubated with propranolol (10 µM) or phentolamine (10 µM) before exposure to epinephrine. The tubes were gently mixed and placed in an incubator for 15 min.

Stimulation, immunofluorescence staining, and flow cytometric analysis were performed as previously described with minor modifications (1). After incubation, a subset of blood samples were stimulated with FMLP (final concentration, 100 nM). After 10 min, 100 µL of stimulated or unstimulated whole blood was added to saturating concentrations of fluorochrome-conjugated antibodies and stained for 15 min in the dark. The staining procedure was stopped by adding 1.5 mL of lysing solution for 10 min. The samples were then centrifuged (350g at 4°C for 5 min), washed with PBS containing 1% BSA, and centrifuged again. The remaining pellet was resuspended in 500 µL of PBS containing 1% BSA and 1% paraformaldehyde. Flow cytometric "two color" analyses were performed on a FACSCalibur flow cytometer and analyzed with CellQuest 3.1 software (Becton Dickinson, San Jose, CA). Before each measurement, the flow cytometer was calibrated with fluorescence microbeads (Calibrite Beads; Becton Dickinson).

To determine platelet-leukocyte aggregates, the leukocyte subpopulations were differentiated by cell size (forward scatter), granularity (side scatter), and binding of anti-CD45-FITC by using linear scaling. For each sample, 40,000 leukocytes were collected. The leukocyte subgroups were separately gated, and platelet-leukocyte aggregates were defined as cells positive for CD41a and CD45 in these subgroups. The percentage of CD41a-positive conjugates represents the percentage of leukocytes with at least one bound platelet (18).

After incubation, a subset of blood samples was stimulated with FMLP (final concentration, 100 nM), washed, and stained as described above. To determine adhesion molecule expression, the leukocyte subpopulations were differentiated by cell size (forward scatter), granularity (side scatter), and binding of anti-CD45-FITC by using linear scaling. For each sample, 40,000 leukocytes were collected. The leukocyte subgroups were separately gated, and the expression of adhesion molecules was measured as mean fluorescence intensity of the specific antibody on neutrophils.

To determine P-selectin and CD41a expression, the platelet population was adjusted to 20 x 10⁹/L before the staining procedure and was defined in flow cytometry by using size and in CD41a-PE immunofluorescence by using logarithmic scaling. For each sample, 10,000 platelets were measured. The percentage of platelets positive for P-selectin and the mean fluorescence intensity of P-selectin and CD41a were measured (19).

The Kolmogorov-Smirnov test showed that the data were mainly normally distributed. Thus, data are presented as means and sd. Differences between the control samples and the samples exposed to increasing concentrations of epinephrine were evaluated with Student’s t-test (NCSS 6.0.7; NCSS, Kaysville, UT). P < 0.05 was considered significant.

	Results

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Almost all concentrations of epinephrine significantly enhanced the binding of platelets to neutrophils in unstimulated and FMLP-stimulated whole blood (Fig. 1). The enhancing effect of epinephrine on neutrophil-platelet conjugate formation was markedly increased by ß-adrenergic blockade. Interestingly, -adrenergic blockade also led to a small increase in epinephrine-induced platelet-neutrophil adhesion (Fig. 2).

View larger version (24K): [in this window] [in a new window]   Figure 1. Percentage of platelet-neutrophil conjugates in unstimulated and N-formyl-methionyl-leucyl-phenylalanine (FMLP)-stimulated (100 nM) whole blood after incubation with increasing concentrations of epinephrine (10 nM, 100 nM, and 1 µM). Mean and sd are given. *Significantly different (P < 0.05) from control.

View larger version (16K): [in this window] [in a new window]   Figure 2. Effect of epinephrine on platelet-neutrophil conjugate formation (A) and CD11b expression (B) after - or ß-adrenergic blockade with phentolamine or propranolol. Data are shown as mean and sd. *Significantly different (P < 0.05) from control.

Epinephrine did not modify CD11b or L-selectin expression on unstimulated neutrophils. Nevertheless, after ß-adrenergic blockade, the incubation with epinephrine caused a significant increase in CD11b expression on unstimulated neutrophils. -Adrenergic blockade also caused a small increase in CD11b expression (Fig. 2). In FMLP-stimulated neutrophils, epinephrine inhibited the FMLP-induced increase in CD11b expression. This inhibition was completely reversed by ß-adrenergic blockade but not by -adrenergic blockade (Table 1).

L-selectin expression in unstimulated blood was not modified by epinephrine. FMLP-stimulated neutrophils showed an increased expression or reduced shedding of L-selectin after incubation with epinephrine. Preincubation with propranolol abolished this effect almost completely, whereas phentolamine caused only a partial decline in L-selectin expression (Table 1). PSGL-1 did not show any significant changes in surface expression (Table 1).

Epinephrine enhanced the expression of P-selectin and GPIIb/IIIa on unstimulated platelets. -Adrenergic blockade with phentolamine before incubation with epinephrine abolished this increase almost completely, whereas ß-adrenergic blockade caused a marked increase in both P-selectin and GPIIb/IIIa expression (Table 1, Fig. 3).

View larger version (16K): [in this window] [in a new window]   Figure 3. Effect of epinephrine on P-selectin (A) and glycoprotein (GP)IIb/IIIa expression (B) on platelets after - or ß-adrenergic blockade with phentolamine or propranolol. Data are expressed as mean and sd. *Significantly different (P < 0.05) from control.

Because -adrenergic blockade with phentolamine preceding incubation with epinephrine also led to a small increase in platelet-neutrophil adhesion and CD11b expression, we added some measurements with phentolamine only. Interestingly, phentolamine alone also enhanced CD11b expression and, concomitantly, platelet-neutrophil aggregate formation, whereas all other platelet and neutrophil adhesion molecules remained unchanged (Table 2). The other measurements with epinephrine alone and epinephrine plus phentolamine corresponded to the results described above.

	Discussion

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This study demonstrates that platelet-neutrophil conjugate formation is enhanced by epinephrine. This increased adhesion was accompanied by an altered adhesion molecule pattern and was modified by - and ß-adrenergic blockade.

Several in vitro and in vivo studies suggest that adrenergic receptor stimulation on immune cells can substantially alter a variety of cellular activities, as well as the release of inflammatory mediators. Epinephrine increases neutrophil recruitment into peripheral blood by an -adrenergic stimulus. There is also evidence that epinephrine decreases neutrophil adherence, chemotaxis, and phagocytic capacity (8–10). ß-Adrenergic agonists inhibit the production of proinflammatory mediators such as TNF-, IL-1, and IL-12, but they augment L-selectin expression and the release of the antiinflammatory substances IL-10 and IL-6. Stimulation of ₂-adrenoceptors increases the release of TNF- and IL-1ß, whereas inhibition of ₂-adrenoceptors enhances the release of the antiinflammatory molecules IL-6 and IL-10 and suppresses the production of TNF- and IL-12 (20–22). In platelets, it has also been shown that epinephrine can potentiate platelet activation and aggregation by activating platelet ₂-adrenoceptors (17).

On the basis of these findings, we hypothesized that epinephrine also influences the regulation of the cell-to-cell interaction between platelets and neutrophils. We first evaluated the effect of epinephrine on the formation of platelet-neutrophil aggregates and found that increasing concentrations of epinephrine enhanced the binding of platelets to neutrophils. This increase in platelet-neutrophil aggregation was accompanied by a significant increase in P-selectin and GPIIb/IIIa expression on platelets. P-selectin is a GP located in the membranes of -granules and becomes externalized on the platelet surface after platelet activation and granule secretion. Platelets and leukocytes may form aggregates via platelet-expressed P-selectin and its counterreceptors PSGL-1 and Sialyl Lewis X, as well as via fibrinogen bridging between GPIIb/IIIa and CD11b (23,24). The initial interactions between neutrophils and platelets are probably mediated by P-selectin, whereas both 1) development of firm adhesion after initial tethering and rolling on P-selectin and 2) transplatelet emigration to chemoattractants seem to be entirely dependent on CD11b (6). Activation of platelets typically enhances P-selectin and GPIIb/IIIa expression, so epinephrine-induced platelet activation could account for the increased formation of conjugates. This could explain our finding that after stimulation with FMLP, epinephrine inhibited the CD11b upregulation but not the formation of neutrophil-platelet aggregates. Because previous studies have shown that platelets are activated via ₂-adrenergic stimulation, we suppose that epinephrine caused the increased adhesion molecule expression via -adrenergic stimulation as well. This is consistent with our finding that -adrenergic blockade with phentolamine before incubation with epinephrine almost completely reversed the observed upregulation of P-selectin and GPIIb/IIIa in platelets.

In neutrophils, the effects of epinephrine after - or ß-adrenergic blockade were more complex. ß-Adrenergic blockade with propranolol before incubation with epinephrine noticeably increased platelet-neutrophil adhesion and CD11b expression. The markedly increased platelet-neutrophil aggregates after ß-adrenergic blockade are probably caused not by the enhanced platelet adhesion molecule expression alone, but also by the CD11b expression on neutrophils. Because ß-adrenergic stimulation—in contrast to -adrenergic stimulation—suppresses leukocyte function, this enhancement may be a consequence of abolition of ß-receptor-mediated suppression of leukocyte function and increased -receptor-mediated stimulation. Interestingly, -adrenergic blockade with phentolamine preceding incubation with epinephrine also led to a small increase in platelet-neutrophil adhesion and CD11b expression. Because this was in contrast to our other results and to the reported suppressing effects of -blockade on leukocyte function, we added some measurements incubating whole blood with phentolamine only. We found the same increase in platelet-neutrophil conjugates and CD11b, whereas all other variables (L-selectin, P-selectin, and GPIIb/IIIa) remained unchanged. Therefore, it seems possible that phentolamine activated neutrophil CD11b expression by a mechanism independent of its ability to antagonize -adrenergic receptors. The increased CD11b expression accompanying neutrophil activation could account for the increased platelet-neutrophil adhesion after phentolamine. However, further research is needed on phentolamine’s effects and the involvement of -adrenergic receptors in neutrophil integrin expression.

The different immunomodulatory effects of - or ß-adrenergic stimulation are probably due to activation of different intracellular pathways. On the molecular level, -adrenergic stimulation most likely results in an activation of nuclear factor-B through activation of protein kinase C and increased intracellular Ca²⁺, whereas ß-adrenergic stimulation leads to an increase of cyclic adenosine monophosphate, which activates protein kinase A. Activated protein kinase A is translocated to the nucleus and blocks nuclear factor-B while activating the cyclic adenosine monophosphate-responsive element-binding protein. Therefore, - or ß-adrenergic stimulation can have markedly different downstream effects (25–28).

Our study showed that epinephrine enhanced platelet-neutrophil adhesion, probably through -adrenergic stimulation of both cell types. Considering the proinflammatory potential of platelet-neutrophil aggregates, our study supports previous studies, which could show that ligation to the -adrenergic receptor is associated with predominantly immunostimulating effects, whereas stimulation of the ß-adrenergic receptor mostly has immunosuppressive effects (29,30). Whereas in the case of cytokine liberation, the ß-adrenoceptor-mediated effects usually override those induced by -adrenoceptor stimulation, it seems that in platelet-neutrophil conjugation, the enhancing -adrenergic effects—predominantly on platelets—outweighed the ß-adrenergic effects. The adhesion between platelets and neutrophils is a key event in thrombosis and inflammation (31). Binding of activated platelets to neutrophils induces respiratory burst and mediates initial neutrophil attachment and rolling, which may lead to neutrophil accumulation at sites of injury (32,33). Therefore, enhanced adhesion after the administration of epinephrine could be crucial for patients with myocardial infarction, trauma, or sepsis. Gawaz et al. (3) also showed that in septic patients, platelet-neutrophil adhesion was an independent predictor for poor clinical outcome. We studied epinephrine concentrations ranging from small therapeutic to supramaximal concentrations, and although the largest amount of conjugates was observed after stimulation with the rather supramaximal epinephrine concentration, it should be noticed that even smaller therapeutic concentrations significantly enhanced platelet-neutrophil adhesion. Nevertheless, the clinical aspects and therapeutic consequences of the enhancing effects of epinephrine on platelet-neutrophil adhesion and adhesion molecule expression in our study remain speculative. First, the therapeutic use of epinephrine is normally required by the hemodynamic state of the patients, which often does not leave much choice for therapeutic alternatives. Second, considering the complex immunomodulatory effects of -or ß-adrenergic stimulation, there are still no data available indicating potential beneficial or detrimental consequences at different stages of disease.

Finally, there are limitations to our study. In contrast to previous studies, we used whole blood instead of isolated neutrophils or platelet-rich plasma, which has the advantages that possibly important influences and interactions of other blood cells and plasma components are not neglected and that artificial cell activation caused by the isolation process is avoided. However, the value of this system is limited by its static condition and the lack of endothelial cells. Therefore, additional in vivo studies or studies with a dynamic model are necessary to further define the role of epinephrine in modulating platelet-neutrophil interaction and adhesion molecule expression and the clinical relevance of our findings. Nonetheless, our study adds another aspect to the understanding of the immunological side effects of endogenous or therapeutically increased catecholamine levels.

The authors thank Nicole Heussen, Department of Biometry and Statistics, Rheinisch-Westfälische Technische Hochschule Aachen, for her statistical advice.

	Footnotes

 
Accepted for publication July 21, 2004.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Horn, N. A. Articles by Rossaint, R. Search for Related Content PubMed PubMed Citation Articles by Horn, N. A. Articles by Rossaint, R.