Eicosanoids pp 89-97 | Cite as

Polymorphonuclear-Endothelial Cell Interactions and the Control of Coronary Vasculature

  • Angelo Sala
Part of the NATO ASI Series book series (NSSA, volume 283)


The generation of leukotrienes (LTs) exhibits remarkable cellular specificity; both PMNL and eosinophils contain the 5-lipoxygenase (5-LO) enzyme, a single protein possessing both the dioxygenase activity necessary for the synthesis of 5-hydroperoxy eicosatetraenoic acid (5-HPETE), and the epoxygenase activity leading to leukotriene A4 (LTA4)(Shimizu et al, 1984). This unstable allylic epoxide can be further converted by secondary enzymes, i.e. LTA4 hydrolase and leukotriene C4 (LTC4) synthase, into leukotriene B4 (LTB4) or LTC4 respectively (Lewis & Austen, 1984). Following challenge with the calcium ionophore A23187 (Borgeat & Samuelsson, 1979), PMNL generate predominantly LTB4, a compound with very potent chemoattractant activities. On the other hand eosinophils (Weller et al., 1983) show preferential generation of LTC4, a potent bronchoconstrictor. Recently it has been shown that the two biosynthetic steps leading to bioactive leukotrienes, can be carried out by different cell types, whereby PMNL (i.e. donor cells) can synthesize the unstable metabolic intermediate LTA4 which can be metabolized by vicinal cells (i.e. acceptor cells) into LTs B4 or C4. Such reaction involves the cooperation of PMNL with erythrocytes, platelets, endothelial cell (McGee & Fitzpatrick, 1986; Maclouf & Murphy, 1988; Feinmark & Cannon, 1986 and 1987; Marcus et al., 1982). This process has been termed “transcellular biosynthesis” and suggests that the cellular environment (i.e. cell-cell interaction) is an important control in the production of eicosanoids (Maclouf et al., 1989). Most in vitro studies of transcellular biosynthesis have used cells isolated from blood or cultured endothelial cells as a reflection of what might happen in pathological situations such as in inflammatory reactions or in cardiovascular diseases where cell-cell interactions constitute an important part of this process (Lucchesi & Mullane, 1986).


Rabbit Heart Coronary Perfusion Pressure Calcium Ionophore A23187 Coronary Vasculature Isolate Rabbit Heart 
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  1. Borgeat, P. and Samuelsson, B., 1979, Arachidonic acid metabolism in polymorphonuclear leukocytes: effects of ionophore A23187. Proc Natl Acad Sci USA, 76(5), 2148–2152.PubMedCrossRefGoogle Scholar
  2. Brady, H.R. and Serhan, C.N., 1992, Adhesion promotes transcellular leukotriene biosynthesis during neutrophil-glomerular endothelial cell interactions: inhibition by antibodies against CD18 and L-selectin. Biochem Biophys Res Commun, 186, 1307–1314.PubMedCrossRefGoogle Scholar
  3. Carry, M., Korley, V., Willerson, J.T., Weigelt, L., Ford-Hutchinson, A.W. and Tagari, P., 1992, Incresed urinary excretion in patients with cardiac ischemia. In vivo evidence for 5-lipoxygenase activation. Circulation, 85, 230–236.PubMedCrossRefGoogle Scholar
  4. Claesson H.E. and Haeggström J., 1988, Human endothelial cells stimulate leukotriene synthesis and convert granulocyte-released leukotriene A4 into leukotrienes B4, C4, D4 and E4. Eur J Biochem, 173, 93–100.PubMedCrossRefGoogle Scholar
  5. Dahlen, S.E., Bjork, J., Hedquist, P., et al., 1981, Leukotriene promote plasma leakage and leukocyte adhesion in post-capillary venules: in vivo effects with relevance to the acute inflammatory response. Proc Natl Acad Sci USA, 78:3887–3891.PubMedCrossRefGoogle Scholar
  6. Evers, A.S., Murphree, S., Saffitz, J.E., Jakschik, B.A. and Needleman, P., 1985, Effects of endogenously produced leukotrienes, thromboxane and prostaglandins on coronary vascular resistance in rabbit myocardial infarction. J Clin Invest, 75, 992–999.PubMedCrossRefGoogle Scholar
  7. Feinmark, S.J. and Cannon, P.J., 1986, Endothelial cell leukotriene C4 synthesis results from intracellular transfer of leukotriene A4 synthesized by polymorphonuclear leukocytes. J Biol Chem, 261, 16466–16472.PubMedGoogle Scholar
  8. Feinmark, S.J. and Canno, P.J., 1987, Vascular smooth muscle cells leukotriene C4 synthesis: requirement for transcellular leukotriene A4 metabolism. Biochim Biophys Acta, 922, 125–135.PubMedCrossRefGoogle Scholar
  9. Fleish, J.H., Rinkema, L.E., Haisch, K.D., Swanson-Bean. D., Goodson, T., Ho, P.P.K. and Marshall, W.S., 1985, LY171883,1-(2-hydroxy-3-propyl-4-(4-(1H-tetrazol-5yl)butoxy) phenyl)ethanone, an orally active leukotriene D4 antagonist. J Pharmacol Exp Therap, 233(1), 148–157.Google Scholar
  10. Gillard, J., Ford-Hutchinson, A.W., Chan, C., Charleson, S., Denis, D., Foster, A., Leger, S., McFarlane, C.S., Morton, H., Piechuta, H., Riendeau, D., Rouzer, CA., Rokach, J., Young, R., MacIntyre, D.E., Peterson, L., Bach, T., Eiermann, G., Hopple, S., Humes, J., Hupe, L., Luell, S., Metzger, J., Meurer, R., Miller, D.K,. Opas, E. and Pacholok, S., 1989, L-663,536 (MK-886) (3-(1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropyilndol-2-yl)-2,2-dimethylpropanoic acid), a novel orally active leukotriene biosynthesis inhibitor. Can J Physiol Pharmacol, 67(5), 456–464.PubMedCrossRefGoogle Scholar
  11. Grimminger, F., Kreusler, B., Schneider, U., Becker, G. and Seeger, W., 1990, Influence of microvascular adherence on neutrophil leukotriene generation. J Immunol, 144, 1866–1872.PubMedGoogle Scholar
  12. Hatzelmann, A., Fruchtmann, R., Mohrs, K.H., Raddatz, S. and Müller-Peddinghaus, R., 1993, Mode of action of the new selective leukotriene synthesis inhibitor BAY X1005 ((R)-2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentyl acetic acid and structurally related compounds. Biochem Pharmacol, 45, 101–111PubMedCrossRefGoogle Scholar
  13. Hock, C.E., Beck, L.D. and Papa, L.A., 1992, Peptide leukotriene receptor antagonism in myocardial ischemia and reperfusion. Cardiovascular Research, 26, 1206–1211.PubMedCrossRefGoogle Scholar
  14. Hynes, R.O., 1987, Integrins: a family of cell surface receptors. Cell, 48, 549–557.PubMedCrossRefGoogle Scholar
  15. Johnston, G.I., Bliss, G.A., Newman, P.J. and McEver, R.P., 1990, Structure of the human gene encoding granule membrane protein-140, a member of the selectin family of adhesion receptors for leukocytes. J Biol Chem, 265(34), 21381–21385.PubMedGoogle Scholar
  16. Kubes, P., Suzuki, M. and Granger, D.N., 1991, Nitric oxide: An endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci, 88, 4651–4655.PubMedCrossRefGoogle Scholar
  17. Lewis, R.A. and Austen, K.F., 1984, The biologically active leukotrienes: biosynthesis, metabolism, receptors, functions and pharmacology. J Clin Invest, 73, 889–897.PubMedCrossRefGoogle Scholar
  18. Lo, S.K., Everitt, J., Gu, J. and Malik, A.B., 1992, Tumor Necrosis Factor Mediates Experimental Pulmonary Edema by ICAM-1 and CD18-dependent Mechanisms. J Clin Invest, 89, 981–988.PubMedCrossRefGoogle Scholar
  19. Lucchesi, B.R. and Mullane, K.M., 1986, Leukocytes and ischemia-induced myocardial injury. Ann Rev Pharmacol Toxicol, 26, 201–224CrossRefGoogle Scholar
  20. Maclouf, J.A. and Murphy, R.C., 1988, Transcellular metabolism of neutrophil-derived leukotriene A4 by human platelets. J Biol Chem, 263, 174–181.PubMedGoogle Scholar
  21. Maclouf, J., Murphy, R.C. and Henson, P., 1989, Transcellular sulfidopeptide leukotriene biosynthetic capacity of vascular cells. Blood, 74(2), 703–707.PubMedGoogle Scholar
  22. Marcus, A.J., Broekman, M.J., Safier, L.B., Ullman, H.L., Islam, N., Serhan, C.N., Rutherford, L.E., Korchak, H.M. and Weissman, G., 1982, Formation of leukotriene and other hydroxyacids during platelet-neutrophil interactions in vitro. Biochem Biophys Res Commun, 109, 130–138.PubMedCrossRefGoogle Scholar
  23. McGee, J.E. and Fitzpatrick, F.A., 1986, Erythrocyte-neutrophil interaction: formation of leukotriene B4 by transcellular biosynthesis. Proc Natl Acad Sci USA, 83, 1349–1353.PubMedCrossRefGoogle Scholar
  24. Michelassi, F., Landa, L., Hill, R.D., Lowenstein, E., Watkins, W.D., Petkau, A.J. and Zapol, W.M., 1982, Leukotriene D4: a potent coronary artery vasoconstrictor associated with impaired ventricular contraction. Science, 217, 841–843.PubMedCrossRefGoogle Scholar
  25. Mong, S., Wu, H.L., Miller, J., Hall, R.F., Gleason, J.G. and Crooke, S.T., 1987, SKF104353, a high affinity antagonist for human and guinea-pig lung LTD4 receptor, blocked phosphatidylinositol metabolism and thromboxane synthesis induced by leukotriene D4. Mol Pharmacol, 32, 223–229.PubMedGoogle Scholar
  26. Mullane, K., 1988, Myocardial ischemia-reperfusion injury: role of neutrophils and neutrophil derived mediators. In Human Inflammatory Disease-Clinical Immunology, ed. Marone, G., Lichtenstein, L.M., Condorelli, M. and Fauci, A.S. pp 143–160. Toronto-Philadelphia: B.C. Decker Inc.Google Scholar
  27. Palmentier, R., Krump, E., Rocheleau, H., Laviolette, M. and Borgeat, P., 1995, Dynamics of 5-lipoxygenase product synthesis by human neutrophils and eosinophils in plasma and salt solution (HBSS). Inflammation Res, 44(Suppl. 3), S259.Google Scholar
  28. Piper, P.J. and Samhoun, M.N., 1987, Leukotrienes. Brit Med Bull, 43(2), 297–311.PubMedGoogle Scholar
  29. Rossoni, G., Sala, A., Berti, F., Testa, T., Buccellati, C., Müller-Peddinghaus, R., Maclouf, J. and Folco, G.C., 1996, Myocardial protection by the leukotriene synthesis inhibitor BAY X1005; importance of transcellular biosynthesis of cysteinyl-leukotrienes. J Pharmacol Exp Therap, 276, 335–341.Google Scholar
  30. Roth, D.M. and Lefer, A.M., 1983, Studies on the mechanism of leukotriene induced coronary artery constriction. Prostaglandins, 26(4), 573–581.PubMedGoogle Scholar
  31. Sala, A., Aliev, G.M., Rossoni, G., Berti, F., Buccellati, C., Burnstock, G., Folco, G.C. and Maclouf, J., 1996, Morphological and functional changes of coronary vasculature caused by transcellular biosynthesis of sulfidopeptide leukotrienes in isolated heart of rabbit. Blood, press., 87 (5)Google Scholar
  32. Sala, A., Rossoni, G., Buccellati, C., Berti, F., Maclouf, J. and Folco, G.C., 1993, Formation of sulfidopeptide-leukotrienes by cell-cell interaction causes coronary vasoconstriction in isolated, cell-perfused rabbit heart. Br J Pharmacol, 110, 1206–1212.PubMedCrossRefGoogle Scholar
  33. Schror, K. Cytoprotective properties of prostacyclin., 1992, In: Rubanyi, G.M., Vane, J. (eds). Prostacyclin: new perspectives for basic research and novel therapeutic indication. Amsterdam: Elsevier, 157–168.Google Scholar
  34. Shimizu, T., Rådmark, O. and Samuelsson, B., 1984, Enzyme with dual lipoxygenase activities catalyzes leukotriene A4 synthesis from arachidonic acid. Proc. Natl. Acad. Sci. USA, 81: 689–693.PubMedCrossRefGoogle Scholar
  35. Sugama, Y., Tiruppati, C., Janakidevi, K., Andersen, T.T., Fenton, J.W. and Malik, A.B., 1992, Thrombin-induced Expression of Endothelial P-Selectin and Intercellular Adhesion Molecule-1: A Mechanism for Stabilizing Neutrophil Adhesion. J Cell Biol, 119(4), 935–944.PubMedCrossRefGoogle Scholar
  36. Vane, J. and Botting, R., 1993, Prostacyclin in perspective. Crit Ischaemia, 3(Suppl.1), 4–13.Google Scholar
  37. Weller, P.F., Lee, C.W., Foster, D.W., Corey, E.J., Austen, K.F. and Lewis, R.A., 1983, Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: predominant production of leukotriene C4. Proc Natl Acad Sci USA, 80, 7626–7630.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Angelo Sala
    • 1
  1. 1.Center for Cardiopulmonary PharmacologyUniversity of MilanMilanItaly

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