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Volume 271, Number 30, Issue of July 26, 1996 pp. 17944-17948
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Release of Leukotriene A₄ Versus Leukotriene B₄ from Human Polymorphonuclear Leukocytes

(Received for publication, March 29, 1996, and in revised form, May 6, 1996)

Angelo Sala , Manlio Bolla , Simona Zarini , Reiner Müller-Peddinghaus and Giancarlo Folco

From the Center for Cardiopulmonary Pharmacology, Institute of Pharmacological Sciences, School of Pharmacy, University of Milano, Via Balzaretti 9, 20133 Milano, Italy and the  Pharma Research Center, Bayer AG, 42096 Wuppertal, Federal Republic of Germany

The reactive intermediate formed by 5-lipoxygenase metabolism of arachidonic acid, leukotriene A₄, is known to be released from cells and subsequently taken up by other cells for biochemical processing. The objective of this study was to determine the relative amount of leukotriene A₄ synthesized by human polymorphonuclear leukocytes (PMNL) that is available for transcellular biosynthetic processes. This was accomplished by diluting cell suspensions and measuring the relative amounts of enzymatic versus nonenzymatic leukotriene A₄-derived metabolites after challenge with the Ca²⁺ ionophore A23187. Nonenzymatic leukotriene A₄-derived metabolites were used as a quantitative index of the amount of leukotriene A₄ released into the extracellular milieu. The results obtained demonstrated that in human PMNL, the relative amounts of nonenzymatic versus enzymatic leukotriene A₄-derived metabolites increased with decreasing cell concentrations. After a 20-fold dilution of PMNL in cell preparations, a doubling in the amount of nonenzymatic leukotriene A₄-derived metabolites was observed following challenge (from 53.9 ± 1.3 to 110.4 ± 8.9 pmol/10⁶ PMNL, p < 0.01). Reduction of possible cell-cell interactions by dilution suggested that over 50% of leukotriene A₄ synthesized is released from the PMNL. These data provide evidence that, in human PMNL preparations, transfer of leukotriene A₄ to neighboring PMNL is taking place, resulting in additional formation of leukotriene B₄ and its -oxidized metabolites 20-hydroxy- and 20-carboxy-leukotriene B₄. Neutrophil reuptake of extracellular leukotriene A₄ leads to an underestimation of the fraction of leukotriene A₄ that is in fact available for transcellular metabolism when tight cell-cell interactions occur, such as during PMNL adhesion to the microvascular endothelium and diapedesis.

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