Thromb Haemost 1999; 81(03): 442-448
DOI: 10.1055/s-0037-1614492
Review Article
Schattauer GmbH

Platelet Contribution to Leukotriene Production in Inflammation: In Vivo Evidence in the Rabbit[*]

Virgilio Evangelista
,
Antonio Celardo
,
Giuseppe Dell’Elba
,
Stefano Manarini
,
Alexander Mironov
1   Morphology Unit, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy
,
Giovanni de Gaetano
,
Chiara Cerletti
› Author Affiliations
This work was performed in the frame of the National Drug Research Programme (Second Phase) of the Ministry of University and Scientific and Technological Research (MURST) and partially supported by the Italian National Research Council (Convenzione CNR – Consorzio Mario Negri Sud).
Further Information

Publication History

Received27 May 1998

Accepted after resubmission10 November 1998

Publication Date:
09 December 2017 (online)

Summary

The contribution of platelets to arachidonic acid transcellular metabolism may represent an important pathway of leukotriene (LT) production. The aim of this study was to investigate the role of platelets on LT production in an acute inflammatory model in the rabbit. Preliminary experiments showed that rabbit whole blood (5 ml) stimulated in vitro with the calcium ionophore A23187 produced LTB4 (52.7 ± 13.9 ng) and the mixed 5,12-DiHETE (7.25 ± 0.75 ng). In A23187-stimulated thrombocytopenic blood, LTB4 was significantly reduced to 19.5 ± 8.6 ng and 5,12-DiHETE was undetectable. Peptido-LTs were undetectable in both conditions. In experiments using washed cells, addition of thrombin-activated platelets to fMLP-activated PMN resulted in the appearance of 5,12-DiHETE and in more than twofold increase of LTB4 synthesis. When 3H-arachidonic acid-labelled platelets were mixed with unlabelled PMN and challenged with fMLP and thrombin, radioactive LTB4 and 5,12-DiHETE were produced, indicating that platelet-derived arachidonic acid was utilized by PMN 5-lipoxygenase. Intravenous infusion of fMLP (2.5 nmol/kg/min) in the rabbit induced marked granulocytopenia, thrombocytopenia and increased TxB2 plasma concentrations within 3 min. Electron microscopy of lungs showed morphologically activated and aggregated platelets occluding the capillary lumen. Activation and recruitment of circulating cells was accompanied by the production of LTB4 (peak levels at 1 min: 30.0 ± 9.5 ng/ml) and LTE4 (peak levels at 10 minutes: 77.8 ± 11.6 ng/ml). The areas under the blood concentrationtime curve (AUC, ng min/ml) corresponded to 812 ± 182 and 3692 ± 658 for LTB4 and LTE4, respectively. In immunologically thrombocytopenic rabbits, the AUC for LTB4 (86.0 ± 23.0) and LTE4 (1165 ± 542) were both significantly different from controls while in rabbits treated with an anti-leukocyte antiserum, both LTB4 and LTE4 were similar to controls. This experimental model provides in vivo evidence that platelets, involved in an acute inflammatory event contribute to the transcellular production of LTs.

* This paper is dedicated to the memory of Jacques A. Maclouf


 
  • References

  • 1 Marcus AJ. Thrombosis and inflammation as multicellular processes: pathophysiologic significance of transcellular metabolism. Blood 1990; 76: 1903-7.
  • 2 Lewis RA, Austen KF, Soberman RJ. Leukotrienes and other products of the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology in human diseases. N Engl J Med 1990; 323: 645-55.
  • 3 Ford-Hutchinson AW, Bray MA, Doig MV, Shipley ME, Smith MJH. Leukotriene B4, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes. Nature 1980; 286: 264-5.
  • 4 Fels AO, Pawlowski NA, Cramer EB, King TKC, Cohn ZA, Scott WA. Human alveolar macrophages produce leukotriene B4 . Proc Natl Acad Sci USA 1982; 79: 7866-70.
  • 5 Williams JD, Czop JK, Austen KF. Release of leukotrienes by human monocytes on stimulation of their phagocytic receptor for particulate activators. J Immunol 1984; 132: 3034-40.
  • 6 Goldyne ME, Burrish GF, Poubelle P, Borgeat P. Arachidonic acid metabolism among human mononuclear leukocytes. J Biol Chem 1984; 259: 8815-9.
  • 7 McGee JE, Fitzpatrick FA. Erythrocyte-neutrophil interactions: formation of leukotriene B4 by transcellular biosynthesis. Proc Natl Acad Sci USA 1986; 83: 1349-53.
  • 8 Marcus AJ, Broekman MJ, Safier LB, Ullman HL, Islam N, Serhan CN, Rutherford LE, Korchak HM, Weissmann G. Formation of leukotrienes and other hydroxy acids during platelet-neutrophil interactions in vitro. Biochem Biophys Res Commun 1982; 109: 130-7.
  • 9 Palmantier R, Borgeat P. Thrombin-activated platelets promote leukotriene B4 synthesis in polymorphonuclear leucocytes stimulated by physiological agonists. Br J Pharmacol 1991; 103: 1909-16.
  • 10 Pong S-S, DeHaven RN. Characterization of a leukotriene D4 receptor in guinea pig lung. Proc Natl Acad Sci USA 1983; 80: 7415-9.
  • 11 Lewis MA, Mong S, Vessella RL, Crooke ST. Identification and characterization of leukotriene D4 receptors in adult and fetal human lung. Biochem Pharmacol 1985; 34: 4311-7.
  • 12 Badr KF, Baylis C, Pfeffer JM, Pfeffer MA, Soberman RJ, Lewis RA, Austen KF, Corey EJ, Brenner BM. Renal and systemic hemodynamic responses to intravenous infusion of leukotriene C4 in the rat. Circ Res 1984; 54: 492-9.
  • 13 Bittl JA, Pfeffer MA, Lewis RA, Mehrotra MM, Corey EJ, Austen KF. Mechanism of the negative inotropic action of leukotrienes C4 and D4 on isolated rat heart. Cardiovasc Res 1985; 19: 426-32.
  • 14 Nichols WW, Mehta JL, Thompson L, Donnelly WH. Synergistic effects of LTC4 and TxA2 on coronary flow and myocardial function. Am J Physiol 1988; 255: H153-H9.
  • 15 Weller PF, Lee CW, Foster DW, Corey EJ, Austen KF, Lewis RA. Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: predominant production of leukotriene C4 . Proc Natl Acad Sci USA 1983; 80: 7626-30.
  • 16 Peters SP, MacGlashan DW, Schulman ES, Schleimer RP, Hayes EC, Rokach J, Adkinson NF, Lichtenstein LM. Arachidonic acid metabolism in purified human lung mast cells. J Immunol 1984; 132: 1972-9.
  • 17 Kurimoto Y, de Weck AL. Dahinden CA: Interleukin 3-dependent mediator release in basophils triggered by C5a. J Exp Med 1989; 170: 467-79.
  • 18 Feinmark SJ, Cannon PJ. Endothelial cell leukotriene C4 synthesis results from intercellular transfer of leukotriene A4 synthesized by polymorphonu-clear leukocytes. J Biol Chem 1986; 261: 16466-72.
  • 19 Feinmark SJ, Cannon PJ. Vascular smooth muscle cell leukotriene C4 synthesis: requirement for transcellular leukotriene A4 metabolism. Biochim Biophys Acta 1987; 922: 125-35.
  • 20 Pace-Asciak CR, Klein J, Spielberg SP. Metabolism of leukotriene A4 into C4 by human platelets. Biochim Biophys Acta 1986; 877: 68-74.
  • 21 Maclouf JA, Murphy RC. Transcellular metabolism of neutrophil-derived leukotriene A4 by human platelets. A potential cellular source of leukotriene C4 . J Biol Chem 1988; 263: 174-81.
  • 22 Fiore S, Serhan CN. Formation of lipoxins and leukotrienes during receptor-mediated interactions of human platelets and recombinant human granulocyte/macrophage colony-stimulating factor-primed neutrophils. J Exp Med 1990; 172: 1451-7.
  • 23 Brady HR, Serhan CN. Adhesion promotes transcellular leukotriene biosynthesis during neutrophil-glomerular endothelial cell interactions: inhibition by antibodies against CD18 and L-selectin. Biochem Biophys Res Commun 1992; 186: 1307-14.
  • 24 Maugeri N, Evangelista V, Celardo A, Dell'Elba G, Martelli N, Piccardoni P, de Gaetano G, Cerletti C. Polymorphonuclear leukocyte-platelet interaction: role of P-selectin in thromboxane B2 and leukotriene C4 cooperative synthesis. Thromb Haemost 1994; 72: 450-6.
  • 25 Johnson RJ, Alpers CE, Pritzl P, Schulze M, Baker P, Pruchno C, Couser WG. Platelets mediate neutrophil-dependent immune complex nephritis in the rat. J Clin Invest 1988; 82: 1225-35.
  • 26 Issekutz AC, Ripley M, Jackson JR. Role of neutrophils in the deposition of platelets during acute inflammation. Lab Invest 1983; 49: 716-24.
  • 27 Wu X, Pippin J, Lefkowitz JB. Platelets and neutrophils are critical to the enhanced glomerular arachidonate metabolism in acute nephrotoxic nephritis in rats. J Clin Invest 1993; 91: 766-73.
  • 28 Bednar M, Smith B, Pinto A, Mullane KM. Neutrophil depletion suppresses 111In-labeled platelet accumulation in infarcted myocardium. J Cardiovasc Pharmacol 1985; 7: 906-12.
  • 29 Fletcher MP, Stahl GL, Longhurst JC. C5a-induced myocardial ischemia: role of CD18-dependent PMN localization and PMN-platelet interactions. Am J Physiol 1993; 265: H1750-H61.
  • 30 Schaub RG, Simmons CA, Koets MH, Romano II PJ, Stewart GJ. Early events in the formation of a venous thrombus following local trauma and stasis. Lab Invest 1984; 51: 218-24.
  • 31 Merhi Y, Lacoste L-L, Lam JYT. Neutrophil implications in platelet deposition and vasoconstriction after deep arterial injury by angioplasty in pigs. Circulation 1994; 90: 997-1002.
  • 32 Papayanni A, Serhan CN, Phillips ML, Rennke HG, Brady HR. Transcellular biosynthesis of lipoxin A4 during adhesion of platelets and neutrophils in experimental immune complex glomerulonephritis. Kidney Intl 1995; 47: 1295-1302.
  • 33 Mayadas TN, Mendrick DL, Brady HR, Tang T, Papayanni A, Assmann KJM, Wagner DD, Hynes RO, Cotran RS. Acute passive anti-glomerular basement membrane nephritis in P-selectin deficient mice. Kidney Intl 1996; 49: 1342-9.
  • 34 Brezinski DA, Nesto RW, Serhan CN. Angioplasty triggers intracoronary leukotrienes and lipoxin A4. Impact of aspirin therapy. Circulation 1992; 86: 56-63.
  • 35 Levy BD, Bertram S, Tai HH, Israel E, Fisher A, Drazen JM, Serhan CN. Agonist-induced lipoxin A4 generation: detection by a novel lipoxin A4-ELISA. Lipids 1993; 28: 1047-53.
  • 36 Celardo A, Dell'Elba G, Eltantawy ZM, Evangelista V, Cerletti C. Simultaneous determination of leukotrienes B4 and E4 in whole blood and of leukotriene E4 in urine of rabbit by reversed-phase high-performance liquid chromatography. J Chromatogr 1994; 658: 261-9.
  • 37 Giles AR. Guidelines for the use of animals in biomedical research. Thromb Haemost 1987; 58: 1078-84.
  • 38 Maugeri N, Evangelista V, Piccardoni P, Dell’Elba G, Celardo A, de Gaetano G, Cerletti C. Transcellular metabolism of arachidonic acid: increased platelet thromboxane generation in the presence of activated polymorphonuclear leukocytes. Blood 1992; 80: 447-51.
  • 39 Gibaldi M, Perrier D. 2nd ed. Pharmacokinetics, Marcel Dekker; New York: 1982
  • 40 Reid GK, Kargman S, Vickers PJ, Mancini JA, Léveillé C, Ethier D, Miller DK, Gillard JW, Dixon RAF, Evans JF. Correlation between expression of 5-lipoxygenase-activating protein, 5-lipoxygenase, and cellular leukotriene synthesis. J Biol Chem 1990; 265: 19818-23.
  • 41 Ermert L, Duncker H-R, Rosseau S, Schutte H, Seeger W. Morphometric analysis of pulmonary intracapillary leukocyte pools in ex vivo-perfused rabbit lungs. Am J Physiol 1994; 267: L64-L7.
  • 42 Tagari P, Rasmussen JB, Delorme D, Girard Y, Eriksson L-O, Charleson S, Ford-Hutchinson AW. Comparison of urinary leukotriene E4 and 16-carboxytetranordihydro leukotriene E4 excretion in allergic asthmatics after inhaled antigen. Eicosanoids 1990; 3: 75-80.
  • 43 Fauler J, Tsikas D, Holch M, Seekamp A, Nerlich ML, Sturm J, Frolich JC. Enhanced urinary excretion of leukotriene E4 by patients with multiple trauma with or without adult respiratory distress syndrome. Clin Sci 1991; 80: 497-504.
  • 44 Bresnahan BA, Wu S, Fenoy FJ, Roman RJ, Lianos EA. Mesangial cell immune injury. Hemodynamic role of leukocyte- and platelet-derived eicosanoids. J Clin Invest 1992; 90: 2304-12.
  • 45 Katoh T, Lianos EA, Fukunaga M, Takahashi K, Badr KF. Leukotriene D4 is a mediator of proteinuria and glomerular hemodynamic abnormalities in passive Heymann nephritis. J Clin Invest 1993; 91: 1507-15.
  • 46 Evers AS, Murphree S, Saffitz JE, Jakschik BA, Needleman P. Effects of endogenously produced leukotrienes, thromboxane, and prostaglandins on coronary vascular resistance in rabbit myocardial infarction. J Clin Invest 1985; 75: 992-9.
  • 47 Carry M, Korley V, Willerson JT, Weigelt L, Ford-Hutchinson AW, Tagari P. Increased urinary leukotriene excretion in patients with cardiac ischemia. In vivo evidence for 5-lipoxygenase activation. Circulation 1992; 85: 230-6.
  • 48 Rossoni G, Sala A, Berti F, Testa T, Buccellati C, Molta C, MullerPeddinghaus R, Maclouf J, Folco GC. Myocardial protection by the leukotriene synthesis inhibitor BAY X1005: importance of transcellular biosynthesis of cysteinyl-leukotrienes. JPET 1996; 276: 335-341.