Interaction of Platelets and Neutrophils in the Generation of Sulfidopeptide Leukotrienes
For approximately 50 years the mediator termed slow reacting substance of anaphylaxis (SRS-A) was suspected to play an important role in human allergic reactions, prolonged bronchoconstriction and asthma yet its chemical structure remained elusive (1, 2). Details concerning the biosynthetic origin of this molecule as well as the regulatory mechanisms involved in controlling production and degradation of SRS-A were unknown. In 1979, the structure of SRS-A was elucidated (3) as a family of three novel compounds, having both a lipid portion derived from arachidonic acid and a peptide portion derived from glutathione (4). These molecules are now termed sulfidopeptide leukotrienes (leukotriene C4, D4, E4), which differ in the number of amino acid residues resident in the peptide portion as either gamma-glutamylcysteinylglycine, cysteinylglycine, or cysteine respectively. During the past decade, a great deal of information has been obtained describing the biosynthesis of these molecules, the activation of phospholipase A2 in liberating free arachidonic acid esterified to storage phospholipids (5), the importance of 5-lipoxygenase in generating the reactive intermediate leukotriene A4 (6) and LTC4 synthase which catalyzes the condensation of glutathione with leukotriene A4 yielding LTC4 (7). Furthermore, it is now recognized that sulfidopeptide leukotrienes can be synthesized in a variety of cells including mast cells (8), eosinophils (9), macrophages (10), and basophils (11). Interest in these molecules continues because of the potent biological activities which they possess including bronchoconstriction (12), vasoconstriction (13), and increased vascular permeability (14). Metabolism of LTC4 is known to take place rapidly and includes sequential peptide cleavage reactions (leading to the sulfidopeptide leukotriene described above) as well as ω- and β-oxidation with ultimate elimination of metabolites into the urine (15).
KeywordsHuman Neutrophil Lipid Mediator Calcium Ionophore Calcium Ionophore A23187 Human Polymorphonuclear Leukocyte
Unable to display preview. Download preview PDF.
- 1.C. H. Kelloway and E. R. Trethewie, The liberation of a slow-reacting smooth muscle-stimulating substance in anaphylaxis, J. Exptl. Phvsiol. 30: 121 (1940).Google Scholar
- 4.B. Samuelsson, P. Borgeat, S. Hammarstrom, and R. C. Murphy, Leukotrienes: A new group of biologically active compounds, in: “Advances in Prostaglandins and Thromboxane Research,” B. Samuelsson, P. W. Ramwell, and R. Paoletti, eds., Raven Press, New York (1980).Google Scholar
- 21.A. Del Maschio, V. Evangelista, G. Rajtar, Z.-M. Chen, C. Cerletti, and G. De Gaetano, Platelet activation by polymorphonuclear leukocytes exposed to chemotactic agents, Am. J. Phvsiol. 258: H870 (1990).Google Scholar
- 24.S. T. McGarrity, T. M. Hyers, and R. O. Webster, Inhibition of neutrophil functions by platelets and platelet-derived products: Description of multiple inhibitory properties, J. Leuk. Biol. 44: 93 (1988).Google Scholar
- 32.A. J. Marcus, L. B. Safier, H. L. Ullman, N. Islam, M. J. Broekman, N. Islam, T. D. Oglesby, and R. R. Gorman, 12S,20-Dihydroxyicosatetraenoic acid: A new eicosanoid synthesized by neutrophils from 12S-hydroxyicosatetraenoic acid produced by thrombin-or collagen-stimulated platelets, Proc. Natl. Acad. Sci. USA 81: 903 (1984).PubMedCrossRefGoogle Scholar
- 34.A. J. Marcus, L. B. Safier, H. L. Ullman, N. Islam, M. J. Broekman, J. R. Falck, S. Fischer, and C. von Schacky, Platelet-neutrophil interactions: (12S)-hydroxy-eicosatetraen-l, 20-dioic acid: A new eicosanoid synthesized by unstimulated neutrophils from (12S)-20-dihydroxyeicosatetraenoic acid, J. Biol. Chem. 263: 2223 (1988).PubMedGoogle Scholar
- 52.R. C. Murphy and P. M. Henson, Mediator network, in: “Annales de l’Institut Pasteur/Immunologie,” Institut Pasteur, ed., Institut Pasteur (1985).Google Scholar