Informaciones Adicionales
57 Dividend Yield (Dividendos & ICP Distribuidos/ Cotización Media 1 )
platelet activation and granule secretion. Therefore, increased expression of platelet surface P-selectin might induce increased platelet adhesion to circulating leukocytes (19–21).
Following incubation with 2 MAC sevoflurane we found significantly elevated P-selectin expression in unstimulated and TRAP-6-activated platelets. This increased P-selectin expres- sion could be the reason for the enhancing effect of sevoflurane on lymphocyte–platelet adhesion in unstimulated blood and the increased amount of monocyte–platelet conjugates and neutrophil–platelet conjugates in TRAP-6-activated blood (22). Even though the increase in platelets expressing P-selectin following stimulation with ADP was not statistically signifi- cant, it could account for the elevation of lymphocyte–platelet and monocyte–platelet aggre- gates. These findings correspond with the results of Fröhlich et al. (16) who also observed an upregulation of P-selectin on unstimulated platelets following incubation with sevoflurane. Interestingly, this effect of sevoflurane on P-selectin expression is not limited to platelets but has been observed by other study groups on endothelial cells. Morisaki et al. (23) reported increased leukocyte rolling and adhesion in rats undergoing sevoflurane anaesthesia, prob- ably caused by an upregulation of P-selectin expression on endothelial cells.
We found that 2 MAC desflurane inhibited the number of platelet–leukocyte complexes. With the exception of monocyte–platelet adhesion following stimulation with ADP, this ef- fect was observed mainly in the unstimulated samples, so that the impact of desflurane on platelet adhesion might be rather weak, as it was easily overridden by activation. In contrast to sevoflurane, desflurane did not alter the P-selectin expression on platelets. Therefore, it is likely that the inhibitory effect of desflurane is mediated via a non-P-selectin mechanism. Brown et al. (24) showed that blocking antibodies to platelet P-selectin partially inhibited ad- hesion. However, blockade of the neutrophil beta(2) integrin CD11b/CD18 also inhibited the percentage of neutrophils that bound to platelets. This leukocyte–platelet adhesion seems to be mediated by interaction of CD11b/CD18 with fibrinogen bound to GPIIb/IIIa on platelets (25–27). Therefore, it is possible that desflurane interacts with fibrinogen binding between leukocytes and platelets, potentially through modulation of CD11b/CD18 expression on leu- kocytes. However, it remains to be investigated whether desflurane interacts with leukocyte surface glycoprotein expression, thus inhibiting platelet–leukocyte conjugate formation.
What are the clinical relevance of these findings? It is well known that binding of plate- lets, especially to neutrophils and monocytes, plays an important role in the regulation of inflammatory processes. Adhesion of platelets can promote leukocyte rolling, arrest and transmigration as well as liberation of cytokines (IL-1β, IL-18) and the monocyte chemotactic protein (13,14,20).
Pain, stress, necrotic tissue, invading micro-organisms and cardiopulmonary bypass are known modulators of the complex immune response of patients undergoing major surgery. However, anaesthesia and the anaesthetic agents themselves may directly affect the function of immune-competent cells and substantially alter the immune response with a potential
impact on the postoperative course (15,28). However, these actions may only be apparent with high or supraclinical concentrations and/or long-term exposure. There is evidence that long-term sedation with thiopental in neurosurgical patients is associated with infective complications in a dose-dependent manner. At present, no data are available regarding the significance of the observed alterations associated with various anaesthetic procedures in the incidence of postoperative complications associated with an altered immunity.
It is not possible to say whether the observed alterations in our in vitro study on leuko- cyte–platelet complex formation following incubation with sevoflurane or desflurane are associated with postoperative complications related to an altered immunity, as the setting in which the formation of leukocyte–platelet complexes was determined in our study might differ from in vivo conditions. Although, in contrast to other studies we used whole blood in- stead of isolated leukocyte populations – with the advantage that the blood cells are studied in their natural environment with all plasma proteins present and that artificial cell activation caused by the isolation process is avoided.
However, there are some limitations to this study. First, all of the experiments were per- formed under static conditions without taking into account the effects of blood flow, shear rate or stress. Second, stimulation with ADP or TRAP-6 only mimics part of the changes caused by endothelial injury or inflammation (21). Therefore, it is possible that the observed changes in platelet–leukocyte adhesion found in our study are well tolerated in vivo and are without great significance in routine clinical practice. Nevertheless, our study is a first step in the understanding of the effects that volatile anaesthetics may have on the interaction between platelets, leukocytes and cellular immunity. Further work is required to broaden our understanding of these effects, and to examine the exact relevance these may have on clinical practice.
Acknowledgments
This work was supported by START (funds distributed by the scientific board of the Rheinisch- Westfälische Technische Hochschule, Pauwelsstraße 30, 52074 Aachen, Germany).
5
1. Dore M. Platelet–leukocyte interactions. American Heart Journal 1998; 135: 146–51.
2. Walzog B, Gaehtgens P. Adhesion molecules: the path to a new understanding of acute inflamma- tion. News in Physiological Science 2000; 15: 107–13.
3. Cerletti C, Evangelista V, de Gaetano G. Platelet–polymorphonuclear leukocyte functional inter- actions: role of adhesive molecules. Haemostasis 1996; 26: 20–7.
4. Ott I, Neumann FJ, Gawaz M, Schmitt M, Schomig A. Increased neutrophil–platelet adhesion in patients with unstable angina. Circulation 1996; 94: 1239–46.
5. Neumann FJ, Ott I, Gawaz M et al. Cardiac release of cytokines and inflammatory responses in acute myocardial infarction. Circulation 1995; 92: 748–55.
6. May AE, Neumann FJ, Gawaz M, Ott I, Walter H, Schomig A. Reduction of monocyte–platelet in- teraction and monocyte activation in patients receiving antiplatelet therapy after coronary stent implantation. European Heart Journal 1997; 18: 1913.
7. Rinder CS, Bonan JL, Rinder HM, Mathew J, Hines R, Smith BR. Cardiopulmonary bypass induces leukocyte–platelet adhesion. Blood 1992; 79: 1201–5.
8. Palabrica T, Lobb R, Furie B et al. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature 2001; 359: 848–51.
9. de Gaetano G, Cerletti C, Evangelista V. Recent advances in platelet–polymorphonuclear leuko- cyte interaction. Haemostasis 1999; 29: 41–9.
10. Gawaz M, Dickfeld T, Bogner C, Fateh-Moghadam S, Neumann FJ. Platelet function in septic multiple organ dysfunction syndrome. Intensive Care Medicine 1997; 23: 379–85.
11. Salat A, Bodingbauer G, Boehm D et al. Changes of platelet surface antigens in patients suffering from abdominal septic shock. Thrombosis Research 1999; 95: 289–94.
12. Rinder HM, Bonan JL, Rinder CS, Ault KA, Smith BR. Activated and unactivated platelet adhesion to monocytes and neutrophils. Blood 1991; 78: 1760–9.
13. Weyrich AS, Elstad MR, McEver RP et al. Activated platelets signal chemokine synthesis by human monocytes. Journal of Clinical Investigation 1996; 97: 1525–34.
14. Neumann FJ, Marx N, Gawaz M et al. Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets. Circulation 1997; 95: 2387–94.
15. McBride WT, Armstrong MA, McBride SJ. Immuno-modulation: an important concept in modern anaesthesia. Anaesthesia 1996; 51: 465–73.
16. Frohlich D, Rothe G, Schmitz G, Hansen E. Volatile anaesthetics induce changes in the expres- sion of P-selectin and glycoprotein Ib on the surface of platelets in vitro. European Journal of Anaesthesiology 1998; 15: 641–8.
17. Mobert J, Zahler S, Becker BF, Conzen PF. Inhibition of neutrophil activation by volatile anesthet- ics decreases adhesion to cultured human endothelial cells. Anesthesiology 1999; 90: 1372–81. 18. Schmitz G, Rothe G, Ruf A et al. European Working Group on Clinical Cell Analysis: consensus pro-
tocol for the flow cytometric characterisation of platelet function. Thrombosis and Haemostasis 1998; 79: 885–96.
19. Evangelista V, Manarini S, Rotondo S et al. Platelet/polymorphonuclear leukocyte interaction in dynamic conditions: evidence of adhesion cascade and cross talk between P-selectin and the beta 2 integrin CD11b/CD18. Blood 1996; 88: 4183–94.
20. Ruf A, Patscheke H. Platelet-induced neutrophil activation: platelet-expressed fibrinogen induces the oxidative burst in neutrophils by an interaction with CD11C/CD18. British Journal of Haema- tology 1995; 90: 791–6.
21. Escolar G, White JG. Changes in glycoprotein expression after platelet activation: differences between in vitro and in vivo studies. Thrombosis and Haemostasis 2000; 83: 371–86.
22. Rinder HM, Bonan JL, Rinder CS, Ault KA, Smith BR. Dynamics of leukocyte–platelet adhesion in whole blood. Blood 1991; 78: 1730–7.
23. Morisaki H, Suematsu M, Wakabayashi Y et al. Leukocyte–endothelium interaction in the rat mesenteric microcirculation during halothane or sevoflurane anesthesia. Anesthesiology 1997; 87: 591–8.
24. Brown KK, Henson PM, Maclouf J, Moyle M, Ely JA, Worthen GS. Neutrophil–platelet adhesion. Relative roles of platelet P-selectin and neutrophil beta2 (DC18) integrins. American Journal of Respiratory Cell and Molecular Biology 1998; 18: 100–10.
25. Weber C, Springer TA. Neutrophil accumulation on activated, surface-adherent platelets in flow is mediated by interaction of Mac-1 with fibrinogen bound to aIIbb3 and stimulated by platelet- activating factor. Journal of Clinical Investigation 1997; 100: 2085–93.
26. Spangenberg P, Redlich H, Bergmann I, Losche W, Gotzrath M, Kehrel B. The platelet glycoprotein IIb/IIIa complex is involved in the adhesion of activated platelets to leukocytes. Thrombosis and Haemostasis 1993; 70: 514–21.
27. Neumann FJ, Zohlnhofer D, Fakhoury L, Ott I, Gawaz M, Schomig A. Effect of glycoprotein IIb/ IIIa receptor blockade on platelet–leukocyte interaction and surface expression of the leukocyte integrin Mac-1 in acute myocardial infarction. Journal of the American College of Cardiology 1999; 34: 1420–6.
28. Bauer M, Rensing H, Ziegenfuss T. Anesthesia and perioperative immune function. Anaesthesist 1998; 47: 538–56.