Advertisement

Agents and Actions

, Volume 34, Issue 1–2, pp 89–92 | Cite as

PAF and LTB4 biosynthesis in the human neutrophil: Effects of putative inhibitors of phospholipase A2 and specific inhibitors of 5-lipoxygenase

  • K. B. Glaser
  • Y. W. Lock
  • J. Y. Chang
PLA2/5-Lipoxygenase

Abstract

The effect of several putative phospholipase A2 (PLA2) inhibitors on [3H]-acetate incorporation into platelet-activating factor (PAF) upon calcium ionophore A23187 stimulation of purified human neutrophils (PMN) were evaluatedin vitro. PLA2 inhibitors such asp-bromophenacyl bromide (pBPB), ellagic acid, aristolochic acid and gossypol were without effect or only weakly inhibited PAF biosynthesis. Luffariellolide, a potent PLA2 inhibitor isolated from the marine spongeLuffariella sp., dose-dependently inhibited PAF production (IC50=5 μM). Due to the relationship between PAF and LTB4 biosynthesis, the effect of inhibiting LTB4 production on PAF biosynthesis was investigated. At concentrations which reduce LTB4 production by >95%, Wy-50,295 tromethamine and A-64,077, specific 5-lipoxygenase (5-LO) inhibitors, did not significantly effect PAF production. In contrast, L-663,536, the 5-LO translocation inhibitor, was a potent inhibitor of PAF production (IC50=1 μM). This activity of L-663, 536 may contribute to its pharmacological profile at higher doses. These data also suggest that PAF biosynthesis in human PMNs is not dependent on the formation or continued presence of leukotrienes.

Keywords

Gossypol Human Neutrophil Ellagic Acid LTB4 Aristolochic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. [1]
    J. Benveniste, M. Chignard, J. P. LeCouedic and B. B. Vargaftig,Biosynthesis of platelet-activation factor (PAF-Acether) II. Involvement of phospholipase A 2 in the formation of PAF-Acether and lyso-PAF-Acether from rabbit platelets. Thrombosis Res.25, 375–385 (1982).CrossRefGoogle Scholar
  2. [2]
    F. H. Chilton, J. M. Ellis, S. C. Olson and R. L. Wykle,1-0-Alkyl-2-arachidonyl-sn-glycero-3-phosphocholine: a common source of platelet-activating factor and arachidonate in human polymorphonuclear leukocytes. J. Biol. Chem.259, 12014–12019 (1984).PubMedGoogle Scholar
  3. [3]
    H. W. Mueller, J. T. O'Flaherty and R. L. Wykle,Biosynthesis of platelet-activating factor in rabbit polymorphonuclear neutrophils. J. Biol. Chem.258, 6213–6218 (1983).PubMedGoogle Scholar
  4. [4]
    L. A. Marshall, A. Sung, R. Franson and J. Y. Chang,Pharmacological differences of phospholipase A2 purified from human synovial fluid of patients with rheumatoid arthritis and human platelets. FASEB J. 4, A1146 (1990).Google Scholar
  5. [5]
    K. F. Albizati, T. Hohlman, D. J. Faulkner, K. B. Glaser and R. S. Jacobs,Luffariellolide, an anti-inflammatory sesterterpene from the marine sponge Luffariella sp. Experientia43, 949–950 (1987).CrossRefGoogle Scholar
  6. [6]
    M. S. de Carvalho and R. S. Jacobs,Inhibition of eicosanoid release by scalaradial, a phospholipase A 2 inhibitor. The Pharamcologist32, 168 (1990).Google Scholar
  7. [7]
    M. F. Fitzgerald, L. Parente and B. J. R. Whittle,Release of PAF-acether and eicosanoids from guinea-pig alveolar macrophages by FMLP: effect of cyclooxygenase and lipoxygenase inhibition. Eur. J. Pharmacol.164, 539–546 (1989).CrossRefPubMedGoogle Scholar
  8. [8]
    C. A. Rouzer, A. W. Ford-Hutchinson, H. E. Morton and J. W. Gillard,MK 886, a potent and specific leukotriene biosynthesis inhibitor block and reverses the membrane association of 5-lipoxygenase in ionophore-challenged leukocytes. J. Biol. Chem.265, 1436–1442 (1990).PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag 1991

Authors and Affiliations

  • K. B. Glaser
    • 1
  • Y. W. Lock
    • 1
  • J. Y. Chang
    • 1
  1. 1.Division of ImmunopharmacologyWyeth-Ayerst ResearchPrincetonUSA

Personalised recommendations